Volume 2025, Issue 1 8140479

Review Article

Open Access

Cross Talk Between Macrophages and Podocytes in Diabetic Nephropathy: Potential Mechanisms and Novel Therapeutics

Siming Yu

Department of Nephrology II , First Affiliated Hospital of Heilongjiang University of Chinese Medicine , Harbin , 150036 , China , hljucm.edu.cn

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Zehui Han,

Zehui Han

First Clinical Medical College , Heilongjiang University of Chinese Medicine , Harbin , 150040 , China , hljucm.edu.cn

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Chunsheng Li,

Chunsheng Li

First Clinical Medical College , Heilongjiang University of Chinese Medicine , Harbin , 150040 , China , hljucm.edu.cn

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Xinxin Lu,

Xinxin Lu

First Clinical Medical College , Heilongjiang University of Chinese Medicine , Harbin , 150040 , China , hljucm.edu.cn

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Yue Li,

Yue Li

First Clinical Medical College , Heilongjiang University of Chinese Medicine , Harbin , 150040 , China , hljucm.edu.cn

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Xingxing Yuan,

Xingxing Yuan

orcid.org/0000-0002-9894-4127

First Clinical Medical College , Heilongjiang University of Chinese Medicine , Harbin , 150040 , China , hljucm.edu.cn

Department of Gastroenterology , Heilongjiang Academy of Traditional Chinese Medicine , Harbin , 150006 , China , hljtcm.com.cn

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Dandan Guo,

Corresponding Author

Dandan Guo

[email protected]

orcid.org/0009-0006-3007-2883

Department of Cardiology , Second Affiliated Hospital of Heilongjiang University of Chinese Medicine , Harbin , 150001 , China , hljucm.edu.cn

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Siming Yu,

Siming Yu

Department of Nephrology II , First Affiliated Hospital of Heilongjiang University of Chinese Medicine , Harbin , 150036 , China , hljucm.edu.cn

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Zehui Han,

Zehui Han

First Clinical Medical College , Heilongjiang University of Chinese Medicine , Harbin , 150040 , China , hljucm.edu.cn

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Chunsheng Li,

Chunsheng Li

First Clinical Medical College , Heilongjiang University of Chinese Medicine , Harbin , 150040 , China , hljucm.edu.cn

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Xinxin Lu,

Xinxin Lu

First Clinical Medical College , Heilongjiang University of Chinese Medicine , Harbin , 150040 , China , hljucm.edu.cn

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Yue Li,

Yue Li

First Clinical Medical College , Heilongjiang University of Chinese Medicine , Harbin , 150040 , China , hljucm.edu.cn

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Xingxing Yuan,

Xingxing Yuan

orcid.org/0000-0002-9894-4127

First Clinical Medical College , Heilongjiang University of Chinese Medicine , Harbin , 150040 , China , hljucm.edu.cn

Department of Gastroenterology , Heilongjiang Academy of Traditional Chinese Medicine , Harbin , 150006 , China , hljtcm.com.cn

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Dandan Guo,

Corresponding Author

Dandan Guo

[email protected]

orcid.org/0009-0006-3007-2883

Department of Cardiology , Second Affiliated Hospital of Heilongjiang University of Chinese Medicine , Harbin , 150001 , China , hljucm.edu.cn

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First published: 02 May 2025

https://doi.org/10.1155/mi/8140479

Academic Editor: Jia Zhou

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Abstract

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease and end-stage renal failure worldwide. Podocytes, essential components of the glomerular filtration barrier (GFB), are profoundly affected in the diabetic milieu, resulting in structural and functional alterations. Concurrently, macrophages, pivotal innate immune cells, infiltrate the diabetic kidney and exhibit diverse activation states influenced by the local environment, playing a crucial role in kidney physiology and pathology. This review synthesizes current insights into how the dynamic cross talk between these two cell types contributes to the progression of DN, exploring the molecular and cellular mechanisms underlying this interaction, with a particular focus on how macrophages influence podocyte survival through various forms of cell death, including apoptosis, pyroptosis, and autophagy. The review also discusses the potential of targeting macrophages to develop more effective treatments for DN.

1. Introduction

Diabetic nephropathy (DN) is a primary factor in the development of end-stage renal disease, represents a significant public health challenge, affecting millions worldwide [1]. The pathophysiology of DN is complex, involving a myriad of cellular and molecular pathways. The kidney’s glomerulus is essential for the filtration of blood, a process crucial for maintaining homeostasis. Podocytes, with their unique structure and function, are involved in the formation of the glomerular filtration barrier (GFB) [2]. In DN, hyperglycemia and other metabolic disturbances initiate a cascade of events that lead to podocyte injury, characterized by effacement, detachment, and loss of these cells. Moreover, glucose-induced damage to other renal cells, including mesangial cells, endothelial cells, and tubular epithelial cells, results in mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis [3, 4]. These pathological changes disrupt the GFB, leading to proteinuria, a hallmark of DN [5].

Macrophages, multifunctional cells of the innate immune system, are known for their dual roles in both promoting and resolving inflammation [6]. In the diabetic milieu, macrophages infiltrate the kidney and become activated, assuming a spectrum of activation states influenced by the local microenvironment [7]. Tissue-resident macrophages exert various functions in diabetic kidney injuries by secreting cytokines, recruiting peripheral monocytes, and exacerbating renal damage [8]. The cross talk between macrophages and podocytes in DN is mediated through a variety of mechanisms [9, 10]. Under diabetic stress, podocytes release cytokines and chemokines that attract and activate macrophages [11, 12]. Conversely, activated macrophages secrete a range of factors that sculpture podocyte function and further affect their survival by regulating various forms of podocyte death, such as apoptosis, pyroptosis, and autophagy [13–15]. The identification of molecular mechanisms involved in the macrophage–podocyte cross talk opens new avenues for therapeutic intervention.

This review aims to elucidate the current understanding of macrophages and podocytes in renal physiology and DN, highlighting the latest research findings and their implications for the interaction between macrophages and podocytes, as well as for the development of promising therapeutic strategies in this disease.

2. Podocytes in DN

Podocytes are highly specialized glomerular visceral epithelial cells with a unique morphology characterized by a cell body primary processes and interdigitating foot processes (FPs) [16]. The FPs envelop the glomerular capillaries and are connected by the slit diaphragm (SD), a specialized junctional complex essential for filtration. SD proteins consist of nephrin, podocin, and P-cadherin, which form a porous structure allowing selective filtration of blood while preventing protein leakage [17]. The cytoskeleton of podocytes, predominantly composed of actin filaments, undergoes dynamic remodeling in response to various stimuli, ensuring the adaptability and integrity of the GFB [18]. In addition to preventing proteinuria by maintaining the GFB, podocytes secrete various growth factors and cytokines that regulate glomerular function and response to injury [19].

As a hallmark of DN, the loss of podocytes is closely related to the severity of proteinuria and the progression of glomerulosclerosis [20]. At the early stage of DN, glomerular hypertrophy and hyperfiltration occur, imposing additional mechanical stress on podocytes, which leads to podocyte detachment from the glomerular basement membrane and persistent cell damage [21]. Injured podocytes exhibit FP effacement, a morphological alteration reflected by flattening, widening, and retraction of the normally interdigitating FPs, which disrupts the expression and localization of SD proteins, such as nephrin and podocin, impairing of the filtration function of podocytes and causing the leakage of proteins into the urine [22, 23]. Within podocytes, unfolded protein responses and reactive oxygen species (ROS) overproduction are induced under the hyperglycemic environment of diabetes, which further triggers endoplasmic reticulum stress and oxidative stress, causing damage to podocyte DNA, proteins, and lipids, ultimately leading to cellular dysfunction and death [5, 24]. With DN progression, amounts of inflammatory cytokines, like tumor necrosis factor (TNF)-α and interleukin (IL)-1β, are produced in the diabetic milieu, which harm podocytes and disrupt their functions [25]. In response to hyperglycemia, impaired autophagy in podocytes triggers the aggregation of damaged organelles and proteins, which exacerbates cell injury; moreover, several cell death processes, including apoptosis, pyroptosis, necroptosis, and ferroptosis, are enhanced in podocytes, which are regarded as the major contributors for podocyte loss in DN [26, 27].

Therefore, podocyte loss is critically involved in the pathogenesis of DN, undergoing a range of structural and functional changes. Elucidating these pathologic alterations is essential for developing targeted therapies to preserve podocyte function and prevent the progression of DN. In this regard, mitigating podocyte loss in DN represents promising therapeutic strategies for this disease. Presently, multiple cell death modes have been confirmed in podocytes, including apoptosis, pyroptosis, autophagy, necroptosis, and ferroptosis, each contributing to the pathogenesis of DN [27]. Podocyte apoptosis and resulting podocyte loss affect the early stages of diabetic kidney and contribute to diabetic glomerulopathy in both type I and type II diabetes [28]. Pyroptosis is also associated with the loss of podocytes and the glomerular injury in DN [29]. Similarly, high blood glucose levels are believed to impair autophagy, eliciting podocyte dysfunction and GFB damage [30]. Given the high sensitivity of podocytes to ROS, an overproduction of ROS causes irreversible alterations in the structure and function of these cells, leading to necroptosis and ferroptosis, ultimately to the development of DN [31, 32]. Injured podocytes release substantial amounts of proinflammatory cytokines, which recruit monocyte into the renal tissue where they are converted into macrophages that acquire the M1 phenotype under the inflammatory milieu and produce proinflammatory mediators, promoting renal damage and DN progression [6].

3. Macrophages in DN

3.1. Origins and Phenotypes of Macrophages

Macrophages are versatile and dynamic immune cells that exert a crucial function in kidney homeostasis and pathology. These cells reside as stationary cells within tissues from the yolk sac and fetal liver during embryonic development or originating from the differentiation of blood monocytes [33]. Embryonically derived macrophages represent a population of resident kidney macrophages and colonize the renal tissue during its development and continue to proliferate in situ throughout adulthood [34]. Recent study revealed that yolk–sac-derived macrophages gradually increase in number with age and become a significant component of the renal macrophage population in older mice [35]. Postnatally, the kidney macrophage pool is maintained and supplemented by circulating monocytes, which originate from hematopoietic stem cells located in the bone marrow [36]. These monocytes can infiltrate the kidney, especially during inflammation or injury, and differentiate into macrophages [37]. Renal macrophages, therefore, are sustained through both local proliferation and recruitment from circulating progenitors. They exhibit a range of phenotypes and functions that are influenced by the kidney’s microenvironment, playing critical roles in tissue homeostasis, injury response, and repair [38]. Thus, these macrophages possess high plasticity to adapt in different microenvironments.

The traditional dichotomy of M1 (pro-inflammatory) and M2 (anti-inflammatory or reparative) macrophages is an oversimplification, but provides a framework for understanding macrophage function [39]. M1 macrophages, typically induced by interferon (IFN)-γ and lipopolysaccharide (LPS), secrete cytokines like inducible nitric oxide synthase (iNOS), TNF-α, and IL-1β, which trigger pro-inflammatory responses and are associated with kidney injury and fibrosis [40]. In the initial phase of kidney injury, macrophages are stimulated by pathogen-associated molecular patterns, danger-associated molecular patterns, and pro-inflammatory cytokines, differentiating into pro-inflammatory M1 macrophages that aggravate tissue damage [41, 42]. Persistent M1 macrophages activation and resultant inflammatory damage cause a reduced renal function and ultimately fibrosis [43]. M2 macrophages, often induced by IL-4 and IL-13, express markers, such as arginase (Arg)1, CD206, and IL-10, are responsible for inflammation resolution, tissue repair, and fibrosis [44]. Besides, factors such as cytokines, growth factors, and metabolic cues in the renal microenvironment significantly influence macrophage phenotype and function [45]. For example, in response to kidney injury, macrophages transition from pro-inflammatory M1 to a pro-reparative M2 phenotype characterized by expression of Arg1, which is required for the tubular cell proliferation that mediates renal repair [46]. Therefore, macrophages exist along a spectrum of activation states, influenced by the local microenvironment, allowing them to adapt to various physiological and pathological conditions (Figure 1). Of interest, M2 macrophages could be further classified as M2a, M2b, M2c, and M2d subcategories, each characterized by unique cell surface markers, secreted cytokines, and biological functions [47]. However, the role of these M2 macrophage subtypes in DN remains unclear.

Details are in the caption following the image — **Figure 1**
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Origins and phenotypes of macrophages in kidney. Renal macrophages can be originated from the differentiation of blood monocytes derived from hematopoietic stem cells in the bone marrow or exist as resident cells in tissues from early embryonic development. Tissue resident macrophages can be induced to form the M1 phenotype by LPS or IFN-γ stimulation and secrete inflammatory mediators, such as TNF-α and IL-1β, to exert a pro-inflammatory effect; moreover, they can also be transformed into the M2 phenotype activated by IL-4 and IL-13 and promote tissue repair via producing anti-inflammatory cytokines like IL-10 and TGF-β. This macrophage phenotype switch is a reversible and dynamic process in a diseased microenvironment in the DN. IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; TGF, transforming growth factor; TNF, tumor necrosis factor.

3.2. Pathogenic Roles of Macrophages in DN

During DN progression, infiltrating macrophages have emerged in human diabetic kidneys and are linked to the deteriorating renal function observed in patients with DN [9]. It is reported that macrophages are found in both the glomeruli and interstitium of type 2 diabetic patients with DN, with a 2:1 ratio of M1 to M2 types, which are related to interstitial fibrosis, tubular atrophy, glomerulosclerosis, and albuminuria [48]. Further evaluation of the RNA sequencing data of patients with advanced DN indicates a significant increase in macrophage numbers compared to those in patients with early DN and the control [49]. At the early stage of DN, M1 macrophages are recruited into the kidney, while M2 macrophages predominate during the late stage, as evidenced by the M1/M2 ratio peaks at the early stage of DN and subsequent drops in the late stage of DN [50]. These findings suggest that initial M1 macrophages infiltration in the kidney of DN exert pro-inflammatory function and promotes kidney injury; but with disease progression to the late stage, these macrophages locally differentiate to M2 macrophages, which mediate tissue repair and renal fibrosis. Indeed, the transition between M1 and M2 macrophages is regarded as a dynamic process depending on the renal microenvironment during DN progression [51]. Moreover, increased macrophage numbers are accompanied with frequency changes in regulatory T (Treg) cells and T helper 2 (Th2) cells in diabetic kidney tissues [52], indicating that macrophages might influence other immune cells in the kidney microenvironment. Further clarifying the role of various immune components and their cross talk with macrophages are important for understanding the pathogenesis of DN.

It is believed that macrophages exhibit a dynamic range of phenotypes in DN, transitioning from pro-inflammatory M1 to anti-inflammatory M2 [51]. Initially, hyperglycemia is a key driver for the recruitment of macrophages to the kidney, as high glucose (HG) levels stimulate the production of chemokines and adhesion molecules in renal cells, facilitating the migration of macrophages into the renal tissue [53]. Advanced glycation end products (AGEs), formed in the diabetic milieu, subsequently activate macrophages through receptors for AGE, which triggers the release of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, as well as chemokines like monocyte chemotactic protein-1 (MCP-1), contributing to the inflammatory milieu in the kidney [54]. Besides, these pro-inflammatory macrophages produce amounts of ROS and directly cause damage to renal cells and exacerbate inflammation [55]. They also interact with other immune cells, such as T cells and dendritic cells, amplifying the inflammatory response and oxidative stress, leading to glomerular and tubulointerstitial damage [10]. At the later stage after renal injury, various cytokines are generated in the tissue environment, such as IL-4, IL-13, and transforming growth factor (TGF)-β, which are responsible for the activation of M2 macrophages [6]. Hence, there is a shift towards M2 macrophages, which are involved in tissue repair and fibrosis. In response to renal damage, these macrophages secrete cytokines like TGF-β to stimulate the proliferation of myofibroblasts and the accumulation of extracellular matrix components, participating in the repairing process [56]. However, excessive release of fibrotic factors like TGF-β by macrophages induce the epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells, leading to glomerulosclerosis and tubulointerstitial fibrosis [6]. Thus, macrophages represent significant plasticity in DN, with their phenotype influenced by the local microenvironment and disease stage, contributing to both renal injury and fibrosis [9]. Therapeutic strategies aimed at modulating macrophage phenotypic transformation might be promising in slowing the progression of DN.

4. Cross Talk Between Podocytes and Macrophages in DN

4.1. Effects of Podocytes on Macrophage Activation

As a critical event in DN, podocyte damage precedes and triggers macrophage recruitment by releasing factors that attract macrophages to the site of injury [57]. For example, in response to hyperglycemic stress, damaged podocytes produce chemokines such as MCP-1, potent recruiters, and activators of macrophages [58, 59]. An increased expression of vascular endothelial growth factor (VEGF) in podocytes is correlated to infiltration of macrophages in injured glomeruli of diabetic mice, suggesting that VEGF could serve as a chemotactic factor for macrophage migration [12]. In human podocytes treated with growth hormone (GH), the TNF-α signaling is elevated to promote the differentiation of monocytes into macrophages, while inhibiting either GH activity or TNF-α expression in podocytes reduces macrophage recruitment, glomerular injury, and proteinuria [11]. In addition, factors produced by injured podocytes influence the phenotype of macrophages. For instance, podocyte-derived pro-inflammatory cytokines skew macrophages towards the M1 phenotype, exacerbating glomerular inflammation and injury in DN [36]. By the interaction of podocyte-derived ligands with macrophage Toll-like receptors (TLRs), various inflammatory pathways like the nuclear factor (NF)-κB signaling are activated in macrophages, leading to the production of pro-inflammatory cytokines and chemokines and ultimately to the inflammatory milieu in DN [60].

4.2. Effects of Macrophages on Cell Death Pathways of Podocytes

4.2.1. Apoptosis

As a type of programmed cell death, apoptosis can be stimulated by the death receptor pathway and the mitochondrial pathway [61]. During DN progression, chronic hyperglycemia acts as a prominent inducer of podocyte apoptosis. HG leads to the accumulation of AGEs, which bind to receptors on podocytes, triggering apoptotic pathways. For example, the interaction between AGEs and CXC chemokine ligand (CXCL) 9 activates the JAK2/STAT3 pathway in podocytes, further causes reduced levels of Bax/Bcl-2 and activated caspase-3, suggesting that AGEs exert proapoptotic effects in podocytes [62]. Accumulation of AGEs promotes overproduction of ROS and activation of protein kinase C (PKC), both of which mediate podocyte apoptosis [63]. ROS-induced oxidative stress further exacerbates podocyte apoptosis and subsequent loss of podocytes, which contribute to glomerular damage and progression of DN [64].

Macrophages are confirmed to affect podocyte apoptosis. In vitro assays of macrophages and podocytes found that HG induces M1 macrophage phenotype and podocyte apoptosis in a dose-dependent manner and reduces sirtuin 6 (SIRT6) expression; moreover, overexpressing SIRT6 in macrophages activates M2 transformation and protects the podocytes from HG-induced apoptosis, as evidenced by the increased expression levels of Bcl-2 and CD206, as well as by the downregulation of the expression levels of Bax and CD86 [13]. SIRT6 inhibits mitochondrial dysfunction and exerts antiapoptotic effects via stimulating the adenosine monophosphate-activated protein kinase (AMPK) pathway in HG-stimulated podocytes [65]. In fact, AMPK activation is required for the suppression of oxidative stress-mediated apoptosis of podocytes [66]. However, whether macrophages regulate the expression of SIRT6 in podocytes and further affect podocyte apoptosis is elusive. Compared with control rats, podocyte apoptosis increases in STZ-induced diabetic rats, which is related to increased macrophages infiltration in the kidney. Further mechanistic investigations explained that HG-activated M1 macrophages secrete TNF-α, which induces excess ROS generation in podocytes and causes cell apoptosis via activating the p38 mitogen-activated protein kinase (MAPK) pathway [67]. This signaling pathway further activates NF-κB, which increases pro-inflammatory cytokine expression and cell apoptosis in podocytes and renal tissues [68]. Thus, these findings suggest that macrophages can regulate podocyte apoptosis through affecting HG-induced mitochondrial dysfunction and oxidative damage.

4.2.2. Pyroptosis

Unlike apoptosis, pyroptosis is a pro-inflammatory form of cell death, which has significant implications for kidney inflammation and injury in DN. Inflammasomes, particularly the PYD domains-containing protein 3 (NLRP3) inflammasome, play a crucial role in initiating podocyte pyroptosis. Hyperglycemia and oxidative stress in the diabetic milieu activate NLRP3, facilitating the cleavage of pro-caspase-1 into active caspase-1, which then promotes the maturation and secretion of key pro-inflammatory cytokines, IL-1β and IL-18 [69]. Caspase-1 activation also induces the cleavage of gasdermin D (GSDMD). The N-terminal fragment of GSDMD creates pores in the cell membrane, resulting in cell swelling, membrane rupture, and release of inflammatory contents, characteristic of pyroptosis [70]. The cumulative effect of podocyte loss, inflammation, and fibrosis due to pyroptosis contributes to the progression of DN [71].

It has been demonstrated that extracellular vesicles derived from macrophages can trigger cell pyroptosis by activating the NLRP3 inflammasome [72]. Indeed, in HG-stimulated macrophage-derived extracellular vesicles, the level of miR-21-5p is upregulated, which facilitates the production of ROS and activation of inflammatory response in podocytes. Molecular investigation verified that miR-21-5p suppresses the A20 expression, which induces ROS generation and inflammasome activation, provoking podocyte pyroptosis [14]. As a crucial activator of NLRP3, A20 is verified to promote cellular damage and tissue inflammation [73]. Therefore, these results indicate that macrophages can affect podocyte pyroptosis during DN progression.

4.2.3. Autophagy

Autophagy, a cellular process for degrading and recycling cellular components, plays a significant role in podocyte function, particularly in the context of DN. Under diabetic conditions, activated autophagy is initially protective in podocytes, aiming to remove damaged proteins and organelles and mitigate stress-induced damage [74]. However, chronic hyperglycemia can lead to dysregulated autophagy in podocytes and is characterized by either excessive or insufficient autophagic activity, both of which can contribute to podocyte injury and promote the progression of DN [75]. Several signaling pathways, such as mTOR and AMPK, as well as autophagy-related genes (ATGs) like ATG5 and ATG7, are essential for the regulation of autophagic process in podocytes [76].

It is reported that macrophage-derived exosomes contain some gene regulators, like miRNAs, which can regulate ATGs and signaling pathways, and thus, affect autophagy in renal cell, such as mesangial cells and tubular epithelial cells, thereby participating in the development of DN [77, 78]. Consistent with these findings, overexpressed miR-25-3p is observed in M2 macrophage-derived exosomes that effectively ameliorates HG-induced podocytes injury. Further study revealed that miR-25-3p mitigates podocytes injury via triggering podocyte autophagy through suppressing the dual specificity protein phosphatase 1 (DUSP1) expression [15]. Inactivation of DUSP1 causes the increased expression of lipidated microtubule-associated protein light-chain 3 (LC3-II), an autophagy-associated protein, thus, activating cell autophagy [79]. Of interest, dysregulated autophagy in podocytes can trigger apoptosis, leading to podocyte loss, indicating that the balance between autophagy and apoptosis in podocytes is critical for cell survival [80]. Thus, whether macrophages simultaneously regulate autophagy and apoptosis of podocytes during DN progression merit further investigation.

4.2.4. Necroptosis

Necroptosis is characterized by rupture of the cell membrane and the release of intracellular contents, leading to inflammation. This process is primarily mediated through the receptor-interacting protein kinase 1 and 3 (RIPK1/3) and the mixed lineage kinase domain-like protein [81]. In podocytes exposed to HG, activation of these pathways causes membrane disruption and cell death and ultimately leading to the breakdown of the GFB [82, 83]. In the context of DN, hyperglycemia and the resultant oxidative stress are key triggers for necroptosis, which stimulate the necroptosis pathway in podocytes, resulting in podocyte loss [84]. Besides, inflammatory cytokines, like TNF-α, are elevated in DN and participates in the activation of the RIPK1/RIPK3 signaling pathways, thereby potentiating necroptosis in podocytes [85]. Thereby, podocyte necroptosis plays a significant role in the pathogenesis of DN.

A recent study has demonstrated that the causality between macrophage activation and cell necroptosis. It is found that activated Notch1 in macrophage controls the RIPK3-mediated cell necroptosis through activation of β-catenin, suggesting that macrophages are involved in the regulation of necroptosis in surrounding cells [86]. The Notch1 signaling pathway has been demonstrated to affect the differentiation and necroptosis of various cell types [87]. A similar study unveiled that damaged renal tubular epithelial cells in DN recruit macrophages to the site of injury, where the Notch pathway activation in macrophages induces the polarization of M1 macrophages, secreting large amounts of inflammatory cytokines and exacerbating the inflammatory response, which contributes to necroptosis of tubular epithelial cells [88]. It could be presumed that macrophages regulate podocyte necroptosis in DN.

4.2.5. Ferroptosis

Podocyte ferroptosis, a regulated type of cell death marked by iron-dependent lipid peroxidation, is essential in the pathogenesis of DN. In DN, dysregulated iron homeostasis causes iron overload in podocytes, promoting the formation of ROS and lipid radicals [89]. Moreover, hyperglycemia reduces glutathione levels and inhibits the activity of glutathione peroxidase 4, a key enzyme that prevents against lipid peroxidation, exacerbating lipid peroxidation in podocytes [90]. Podocyte ferroptosis facilitates podocyte loss, GFB damage, inflammation, and oxidative stress, all of which are critical factors in the progression of DN. Recent findings suggest that macrophages can transfer mitochondria to the neighboring cells and further mediate cell injury via triggering ferroptosis [91]. Considering the critical role of podocyte ferroptosis in DN, the effects of macrophages on podocyte ferroptosis under diabetic conditions needs to be further elucidated.

Altogether, macrophages determine cell fate of podocytes through affecting multiple cell death processes, including apoptosis, pyroptosis, autophagy, necroptosis, and ferroptosis (Figure 2). Hence, targeting macrophages to prevent against podocyte death may provide promising therapeutics for DN.

5. Regulation of miRNAs on the Cross Talk Between Macrophages and Podocytes in DN

As concluded above, the interplay between macrophages and podocytes plays a significant role in the pathogenesis of DN. MiRNAs, small noncoding RNA molecules that modulate gene expression posttranscriptionally, have emerged as key regulators in this intercellular communication [92]. Recent studies have highlighted the transfer of miRNAs between macrophages and podocytes via extracellular vesicles. Macrophage-derived miRNAs can modulate gene expression in podocytes, influencing processes such as inflammation, fibrosis, and cell survival. For instance, the exosomes from macrophages treated with HG contain elevated levels of miR-21a-5p, which reduce the cell viability and promote the caspase-3-mediated apoptosis of podocytes, leading to glomerular structural damage, proteinuria, and renal dysfunction [93]. In addition, miRNAs derived from macrophages can regulate critical signaling pathways involved in podocyte survival. Zhuang et al. [94] unveiled that exosomes from HG-treated macrophages exacerbate HG-induced podocyte injury, as evidenced by reduced the proliferation capacity and enhanced apoptosis rate of podocytes; moreover, exosomal miR-21a-5p and miR-25-3p are verified to target the TNPO1/ATXN3 signal axis, which is responsible for the podocyte loss and disease progression. Analogously, TLR4 has been identified as a downstream target of miR-93–5p, which is enhanced in exosomes from M2 macrophages and mitigates LPS-induced podocyte apoptosis [95]. Thus, these results indicate that exosomal miRNAs derived from macrophages can affect podocyte survival (Figure 3).

In conclusion, targeting specific miRNAs offers a novel therapeutic approach for DN. miRNA mimics or inhibitors can be used to restore normal miRNA function or to inhibit the action of miRNAs implicated in disease pathogenesis.

6. Targeting Macrophages as Therapeutic Strategies for DN

Macrophages play a pivotal role in modulating podocyte injury and contribute to inflammation and fibrosis, which have been implicated in the pathogenesis of DN. Consequently, targeting macrophages to prevent against HG-induced podocyte loss presents a promising therapeutic strategy for DN (Table 1).

Table 1. Interventions for modulating macrophage polarization and activation in DN.

Intervention	Target in macrophages	Related signaling pathways or cytokines	Outcome	Ref.
Gene modification	NGAL↑	IL-10↑; TNF-α, IL-1β, TGF-β1↓	Reducing podocyte loss, albuminuria, and renal fibrosis	[96]
Gene modification	Angptl3↓	NLRP3, IL-1β↓	Attenuating podocyte EMT and renal dysfunction	[97]
Gene modification	COX-2↓	iNOS, NF-κB↑; IL-4Rα↓	Promoting endoplasmic reticulum stress and of podocyte loss	[98]
Calcitriol	Unknown	iNOS, TNF-α↓	Ameliorating podocyte injury, proteinuria, and renal damage	[99]
TKL	Notch↓	L-10↑; iNOS, TNF-α↓	Increasing proliferation potential of podocytes and restoring renal function and structure	[100]
Thalidomide	Unknown	TNF-α, IL-1β↓	Reducing HG-induced podocyte injury	[101]
Hyperoside	Unknown	Arg-1↑; MCP-1, iNOS, TNF-α↓	Lessening albuminuria and glomerular mesangial matrix expansion	[102]
Gene modification	Tim-3↓	NF-κB/TNF-α↓	Ameliorating diabetic renal injury	[103]
ISO-1	MIF↓	TNF-α, IL-1β, IL-6↓	Blocking podocyte damage and albuminuria	[104]
Gene modification	CCKR↓	TNF-α↓	Mitigating podocyte loss, albuminuria, and inflammation	[105]

Note: ↑ indicates upregulation and ↓ indicates downregulation.
Abbreviations: Angptl3, angiopoietin-like protein 3; Arg, arginase; CCKR, cholecystokinin receptor; COX, cyclooxygenase; EMT, epithelial-to-mesenchymal transition; HG, high glucose; IL, interleukin; IL-4Rα, interleukin-4 receptor-α; iNOS, inducible nitric oxide synthase; ISO-1, MIF inhibitor; MCP-1, monocyte chemotactic protein-1; MIF, migration inhibitory factor; NF, nuclear factor; NGAL, neutrophil gelatinase-associated lipocalin; NLRP3, NOD-like receptor family pyrin domain containing 3; Tim-3, T cell immunoglobulin and mucin domain-containing protein 3; TKL, Trichosanthes kirilowii lectin; TNF, tumor necrosis factor.

6.1. Modulating Macrophage Polarization

Therapies aimed at modulating macrophage polarization from a pro-inflammatory M1 phenotype to a reparative M2 phenotype can alleviate renal injury in DN. This approach involves targeting specific genes that govern macrophage polarization. For example, genetically modified macrophages stabilized by neutrophil gelatinase-associated lipocalin (NGAL) preserve their M2 phenotype, which elevates anti-inflammatory IL-10 and reduces renal TGF-β1 expression, as well as decreases infiltration of M1 macrophages, thus, mitigating podocyte loss and fibrosis [96]. Likewise, knockout of angiopoietin-like protein 3 drives the transformation of M1 type macrophages into M2 type macrophages, and further attenuates diabetes-related podocyte EMT and renal dysfunction [97]. However, diabetic kidneys with macrophage cyclooxygenase (COX)-2 deletion exhibits an increased M1 macrophage phenotype, which causes renal infiltration of pro-inflammatory cells, endoplasmic reticulum stress, podocytes loss, and fibrosis, developing severe DN [98]. Hence, modulation of macrophage polarization by gene editing can meliorate podocytes loss and DN progression.

Several drugs and natural agents have been shown to affect macrophage polarization and exert a protective role in DN. For instance, calcitriol, a bioactive 1,25-dihydroxyvitamin D3, converts HG-mediated M1 macrophages toward an M2 phenotype in DN rats, thereby reversing podocyte injury [99]. Trichosanthes kirilowii lectin, an herb that exhibits antidiabetic activities, is verified to abate deterioration in renal structure and function of DN rats by increasing the proportion of M2 macrophage through suppression of the Notch signaling [100]. Similarly, thalidomide, a drug for the treatment of plasma cell myeloma, can promote M2 macrophage differentiation by reducing the TNF-α and IL-1β levels, thereby hampering HG-induced podocyte injury [101]. Besides, hyperoside, a traditional Chinese herb with antioxidative, antiapoptotic properties, and podocyte-protective effects, can modulate macrophage polarization by converting pro-inflammatory M1 macrophages into anti-inflammatory M2 ones, repressing renal inflammatory response and production of pro-inflammatory cytokines, such as MCP-1 and TNF-α [102]. Therefore, promoting M2 macrophage transformation via herbs or drugs is effective to protect against podocyte injury.

6.2. Inhibiting the Pro-Inflammatory Activity of Macrophages

In DN, hyperglycemia and the diabetic milieu promote the recruitment and activation of M1 macrophages within the kidney. These activated macrophages secrete pro-inflammatory cytokines, chemokines, and growth factors, exacerbating renal injury. Strategies aimed at inhibiting macrophage recruitment and activation to the kidney have shown promise in mitigating disease progression. To investigate the function of mucin-domain containing-3 (Tim-3) on macrophage activation, Yang et al. [103] revealed that the expression of Tim-3 is increased on renal macrophages in patients with DN, which is associated with renal dysfunction; moreover, upregulated Tim-3 in macrophages expedites podocyte injury via activating the NF-κB/TNF-α signaling pathway. Suppression of macrophage activation through knockdown of Tim-3 alleviates renal damage in DN mice [103]. Coincidentally, administration of DN mice with ISO-1, an inhibitor of macrophage migration inhibitory factor, restrains the activation of macrophages and production of pro-inflammatory cytokines, thus, decreasing podocyte damage and renal fibrosis [104]. Additionally, treatment of sulfated cholecystokinin octapeptide, which exerts renoprotective effects through its anti-inflammatory actions, impedes infiltration of macrophages and expression of pro-inflammatory genes, which reduce podocyte loss and albuminuria in diabetic rats [105]. These findings imply that repression of the activation of pro-inflammatory macrophages decreases podocyte damage and improves renal function.

7. Conclusion and Perspective

As essential components of GFB, podocytes play a pivotal role in the glomerular filtration function and podocyte loss is a key pathological feature in DN. Macrophages are regarded as a kind of versatile innate immune cells, exerting crucial functions in kidney homeostasis and DN progression. The heterogeneity of phenotypes and functions on renal macrophages affect the pathogenesis of DN. A critical aspect of these effects is the cross talk between macrophages and podocytes, wherein macrophages affect podocyte survival by regulating podocyte apoptosis, pyroptosis, autophagy, necroptosis, and ferroptosis. Advances in the research of macrophage-derived miRNAs have revealed complex regulatory networks that govern gene expression and secretion of cytokines and chemokines in podocytes and offers insights into the pathophysiology and potential therapeutics of DN. Hence, targeting macrophages to promote podocyte survival, through modulation of macrophage polarization and inhibition of pro-inflammatory macrophage activation, has emerged as a novel therapeutic strategy. However, the interplay between macrophages and podocytes is highly complex and molecular mechanisms are not fully understood. For example, whether macrophages directly regulate podocyte necroptosis and ferroptosis is still elusive. Besides, effective macrophage-targeted therapies in DN must be specific and safe, minimizing off-target effects while preserving the beneficial roles of macrophages in renal inflammation and tissue repair. Given the multifaceted role of macrophages in regulating podocyte survival, combination therapies that target multiple aspects of DN, including podocyte protection, inflammation reduction, and fibrosis prevention, may offer enhanced therapeutic efficacy. In addition, utilizing genomics, proteomics, and metabolomics to study the cross talk between macrophages and podocytes can provide a more comprehensive understanding of DN pathogenesis.

Nomenclature

AGEs:: Advanced glycation end products
ATGs:: Autophagy-related genes
COX:: Cyclooxygenase
EMT:: Epithelial-to-mesenchymal transition
GSDMD:: Gasdermin D
GH:: Growth hormone
iNOS:: Inducible nitric oxide synthase
IL:: Interleukin
MCP-1:: Monocyte chemotactic protein-1
PKC:: Protein kinase C
ROS:: Reactive oxygen species
SD:: Slit diaphragm
TGF:: Transforming growth factor
VEGF:: Vascular endothelial growth factor
Arg:: Arginase
CXCL:: CXC chemokine ligand
DN:: Diabetic nephropathy
FPs:: Foot processes
GFB:: Glomerular filtration barrier
HG:: High glucose
IFN:: Interferon
miRNAs:: MicroRNAs
NF:: Nuclear factor
NLRP3:: PYD domains-containing protein 3
RIPK:: Receptor-interacting protein kinase
TLRs:: Toll-like receptors
TNF:: Tumor necrosis factor.

Conflicts of Interest

The authors declare no conflicts of interest.

Author Contributions

S. Y. and Z. H. wrote the manuscript. C. L., X. L., and Y. L. contributed to the final manuscript. X. Y. and D. G. verified and discussed the studies. D. G. supervised the study.

Funding

This research is supported by several fundings: Natural Science Foundation Project of Heilongjiang Province (Grant LH2019H112), Traditional Chinese Medicine Research Project of Heilongjiang Province (Grant ZHY2020-121).

Acknowledgments

This research is supported by several fundings: Natural Science Foundation Project of Heilongjiang Province (No. LH2019H112), Traditional Chinese Medicine Research Project of Heilongjiang Province (No. ZHY2020-121). Besides, the manuscript is copyedited by Spring Nature Author Services and no AI software is used to prepare this manuscript.

Open Research

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

1 Mohandes S., Doke T., Hu H., Mukhi D., Dhillon P., and Susztak K., Molecular Pathways that Drive Diabetic Kidney Disease, Journal of Clinical Investigation. (2023) 133, no. 4, https://doi.org/10.1172/JCI165654.
10.1172/JCI165654
PubMed Web of Science® Google Scholar
2 Jiang A., Song A., and Zhang C., Modes of Podocyte Death in Diabetic Kidney Disease: An Update, Journal of Nephrology. (2022) 35, no. 6, 1571–1584, https://doi.org/10.1007/s40620-022-01269-1.
10.1007/s40620-022-01269-1
CAS PubMed Web of Science® Google Scholar
3 Barrera-Chimal J. and Jaisser F., Pathophysiologic Mechanisms in Diabetic Kidney Disease: A Focus on Current and Future Therapeutic Targets, Diabetes, Obesity and Metabolism. (2020) 22, no. S1, 16–31, https://doi.org/10.1111/dom.13969.
10.1111/dom.13969
CAS PubMed Web of Science® Google Scholar
4 Naaman S. C. and Bakris G. L., Diabetic Nephropathy: Update on Pillars of Therapy Slowing Progression, Diabetes Care. (2023) 46, no. 9, 1574–1586, https://doi.org/10.2337/dci23-0030.
10.2337/dci23-0030
PubMed Google Scholar
5 Li X., Zhang Y., and Xing X., et al.Podocyte Injury of Diabetic Nephropathy: Novel Mechanism Discovery and Therapeutic Prospects, Biomedicine & Pharmacotherapy. (2023) 168, https://doi.org/10.1016/j.biopha.2023.115670.
10.1016/j.biopha.2023.115670
Web of Science® Google Scholar
6 Calle P. and Hotter G., Macrophage Phenotype and Fibrosis in Diabetic Nephropathy, International Journal of Molecular Sciences. (2020) 21, no. 8, https://doi.org/10.3390/ijms21082806.
10.3390/ijms21082806
Web of Science® Google Scholar
7 Zhang L., Wen Z., and Han L., et al.Research Progress on the Pathological Mechanisms of Podocytes in Diabetic Nephropathy, Journal of Diabetes Research. (2020) 2020, 15.
10.1155/2020/7504798
Google Scholar
8 Tang P. M., Nikolic-Paterson D. J., and Lan H. Y., Macrophages: Versatile Players in Renal Inflammation and Fibrosis, Nature Reviews Nephrology. (2019) 15, no. 3, 144–158, https://doi.org/10.1038/s41581-019-0110-2, 2-s2.0-85060684529.
10.1038/s41581-019-0110-2
PubMed Web of Science® Google Scholar
9 Yan J., Li X., Liu N., He J. C., and Zhong Y., Relationship between Macrophages and Tissue Microenvironments in Diabetic Kidneys, Biomedicines. (2023) 11, no. 7, https://doi.org/10.3390/biomedicines11071889.
10.3390/biomedicines11071889
Google Scholar
10 Li H. D., You Y. K., and Shao B. Y., et al.Roles and Crosstalks of Macrophages in Diabetic Nephropathy, Frontiers in Immunology. (2022) 13, https://doi.org/10.3389/fimmu.2022.1015142.
10.3389/fimmu.2022.1015142
Google Scholar
11 Nishad R., Mukhi D., and Kethavath S., et al.Podocyte Derived TNF-α Mediates Monocyte Differentiation and Contributes to Glomerular Injury, The FASEB Journal. (2022) 36, no. 12, https://doi.org/10.1096/fj.202200923R.
10.1096/fj.202200923R
PubMed Google Scholar
12 Sato W., Kosugi T., and Zhang L., et al.The Pivotal Role of VEGF on Glomerular Macrophage Infiltration in Advanced Diabetic Nephropathy, Laboratory Investigation. (2008) 88, no. 9, 949–961, https://doi.org/10.1038/labinvest.2008.60, 2-s2.0-50249148344.
10.1038/labinvest.2008.60
CAS PubMed Web of Science® Google Scholar
13 Ji L., Chen Y., and Wang H., et al.Overexpression of Sirt6 Promotes M2 Macrophage Transformation, Alleviating Renal Injury in Diabetic Nephropathy, International Journal of Oncology. (2019) 55, 103–115, https://doi.org/10.3892/ijo.2019.4800, 2-s2.0-85067374282.
10.3892/ijo.2019.4800
CAS PubMed Web of Science® Google Scholar
14 Ding X., Jing N., and Shen A., et al.MiR-21-5p in Macrophage-Derived Extracellular Vesicles Affects Podocyte Pyroptosis in Diabetic Nephropathy by Regulating A20, Journal of Endocrinological Investigation. (2021) 44, no. 6, 1175–1184, https://doi.org/10.1007/s40618-020-01401-7.
10.1007/s40618-020-01401-7
CAS PubMed Web of Science® Google Scholar
15 Huang H., Liu H., and Tang J., et al.M2 Macrophage-Derived Exosomal miR-25-3p Improves High Glucose-Induced Podocytes Injury through Activation Autophagy via Inhibiting DUSP1 Expression, IUBMB Life. (2020) 72, no. 12, 2651–2662, https://doi.org/10.1002/iub.2393.
10.1002/iub.2393
CAS PubMed Web of Science® Google Scholar
16 Pavenstädt H., Kriz W., and Kretzler M., Cell Biology of the Glomerular Podocyte, Physiological Reviews. (2003) 83, no. 1, 253–307, https://doi.org/10.1152/physrev.00020.2002, 2-s2.0-0037207471.
10.1152/physrev.00020.2002
CAS PubMed Web of Science® Google Scholar
17 Gong Y., Sunq A., Roth R. A., and Hou J., Inducible Expression of Claudin-1 in Glomerular Podocytes Generates Aberrant Tight Junctions and Proteinuria through Slit Diaphragm Destabilization, Journal of the American Society of Nephrology. (2017) 28, no. 1, 106–117, https://doi.org/10.1681/ASN.2015121324, 2-s2.0-85021080653.
10.1681/ASN.2015121324
CAS PubMed Web of Science® Google Scholar
18 Wang D., Sant S., and Ferrell N., A Biomimetic In Vitro Model of the Kidney Filtration Barrier Using Tissue-Derived Glomerular Basement Membrane, Advanced Healthcare Materials. (2021) 10, no. 16, https://doi.org/10.1002/adhm.202002275.
10.1002/adhm.202002275
Google Scholar
19 Podgórski P., Konieczny A., Lis Ł., Witkiewicz W., and Hruby Z., Glomerular Podocytes in Diabetic Renal Disease, Advances in Clinical and Experimental Medicine. (2019) 28, no. 12, 1711–1715, https://doi.org/10.17219/acem/104534.
10.17219/acem/104534
Web of Science® Google Scholar
20 Barutta F., Bellini S., and Gruden G., Mechanisms of Podocyte Injury and Implications for Diabetic Nephropathy, Clinical Science. (2022) 136, no. 7, 493–520, https://doi.org/10.1042/CS20210625.
10.1042/CS20210625
Google Scholar
21 Kim J. J., Li J. J., and Jung D. S., et al.Differential Expression of Nephrin According to Glomerular Size in Early Diabetic Kidney Disease, Journal of the American Society of Nephrology. (2007) 18, no. 8, 2303–2310, https://doi.org/10.1681/ASN.2006101145, 2-s2.0-34547616609.
10.1681/ASN.2006101145
CAS PubMed Web of Science® Google Scholar
22 Chen Z., Zhu Z., and Liang W., et al.Reduction of Anaerobic Glycolysis Contributes to Angiotensin II-Induced Podocyte Injury With Foot Process Effacement, Kidney International. (2023) 103, no. 4, 735–748, https://doi.org/10.1016/j.kint.2023.01.007.
10.1016/j.kint.2023.01.007
CAS PubMed Google Scholar
23 Weil E. J., Lemley K. V., and Mason C. C., et al.Podocyte Detachment and Reduced Glomerular Capillary Endothelial Fenestration Promote Kidney Disease in Type 2 Diabetic Nephropathy, Kidney International. (2012) 82, no. 9, 1010–1017, https://doi.org/10.1038/ki.2012.234, 2-s2.0-84867576816.
10.1038/ki.2012.234
PubMed Web of Science® Google Scholar
24 Wang X., Zhao J., Li Y., Rao J., and Xu G., Epigenetics and Endoplasmic Reticulum in Podocytopathy during Diabetic Nephropathy Progression, Frontiers in Immunology. (2022) 13, https://doi.org/10.3389/fimmu.2022.1090989.
10.3389/fimmu.2022.1090989
Google Scholar
25 Wei T. T., Yang L. T., and Guo F., et al.Activation of GPR120 in Podocytes Ameliorates Kidney Fibrosis and Inflammation in Diabetic Nephropathy, Acta Pharmacologica Sinica. (2021) 42, no. 2, 252–263, https://doi.org/10.1038/s41401-020-00520-4.
10.1038/s41401-020-00520-4
CAS PubMed Web of Science® Google Scholar
26 Hartleben B., Gödel M., and Meyer-Schwesinger C., et al.Autophagy Influences Glomerular Disease Susceptibility and Maintains Podocyte Homeostasis in Aging Mice, Journal of Clinical Investigation. (2010) 120, no. 4, 1084–1096, https://doi.org/10.1172/JCI39492, 2-s2.0-77951169411.
10.1172/JCI39492
CAS PubMed Web of Science® Google Scholar
27 Yang C., Zhang Z., and Liu J., et al.Research Progress on Multiple Cell Death Pathways of Podocytes in Diabetic Kidney Disease, Molecular Medicine. (2023) 29, no. 1, https://doi.org/10.1186/s10020-023-00732-4.
10.1186/s10020-023-00732-4
Google Scholar
28 Wang Y., Niu A., and Pan Y., et al.Profile of Podocyte Translatome During Development of Type 2 and Type 1 Diabetic Nephropathy Using Podocyte-Specific TRAP mRNA RNA-Seq, Diabetes. (2021) 70, no. 10, 2377–2390, https://doi.org/10.2337/db21-0110.
10.2337/db21-0110
CAS PubMed Web of Science® Google Scholar
29 Wu J., Raman A., and Coffey N. J., et al.The Key Role of NLRP3 and STING in APOL1-Associated Podocytopathy, Journal of Clinical Investigation. (2021) 131, no. 20, https://doi.org/10.1172/JCI136329.
10.1172/JCI136329
Google Scholar
30 Bork T., Liang W., and Yamahara K., et al.Podocytes Maintain High Basal Levels of Autophagy Independent of Mtor Signaling, Autophagy. (2020) 16, no. 11, 1932–1948, https://doi.org/10.1080/15548627.2019.1705007.
10.1080/15548627.2019.1705007
CAS PubMed Web of Science® Google Scholar
31 Wang H., Liu D., and Zheng B., et al.Emerging Role of Ferroptosis in Diabetic Kidney Disease: Molecular Mechanisms and Therapeutic Opportunities, International Journal of Biological Sciences. (2023) 19, no. 9, 2678–2694, https://doi.org/10.7150/ijbs.81892.
10.7150/ijbs.81892
CAS PubMed Web of Science® Google Scholar
32 Chung H., Lee S. W., and Hyun M., et al.Curcumin Blocks High Glucose-Induced Podocyte Injury via RIPK3-Dependent Pathway, Front Cell Dev Biol. (2022) 10, https://doi.org/10.3389/fcell.2022.800574.
10.3389/fcell.2022.800574
Google Scholar
33 Munro D. A. D. and Hughes J., The Origins and Functions of Tissue-Resident Macrophages in Kidney Development, Frontiers in Physiology. (2017) 8, https://doi.org/10.3389/fphys.2017.00837, 2-s2.0-85032203725.
10.3389/fphys.2017.00837
PubMed Google Scholar
34 Gomez Perdiguero E., Klapproth K., and Schulz C., et al.Tissue-Resident Macrophages Originate from Yolk-Sac-Derived Erythro-Myeloid Progenitors, Nature. (2015) 518, no. 7540, 547–551, https://doi.org/10.1038/nature13989, 2-s2.0-84925465211.
10.1038/nature13989
CAS PubMed Web of Science® Google Scholar
35 Ide S., Yahara Y., and Kobayashi Y., et al.Yolk-Sac-Derived Macrophages Progressively Expand in the Mouse Kidney With Age, Elife. (2020) 9, https://doi.org/10.7554/eLife.51756.
10.7554/eLife.51756
PubMed Google Scholar
36 Ricardo S. D., van Goor H., and Eddy A. A., Macrophage Diversity in Renal Injury and Repair, Journal of Clinical Investigation. (2008) 118, no. 11, 3522–3530, https://doi.org/10.1172/JCI36150, 2-s2.0-55849103960.
10.1172/JCI36150
CAS PubMed Web of Science® Google Scholar
37 Lee S., Huen S., and Nishio H., et al.Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair, Journal of the American Society of Nephrology. (2011) 22, no. 2, 317–326, https://doi.org/10.1681/ASN.2009060615, 2-s2.0-79551654684.
10.1681/ASN.2009060615
CAS PubMed Web of Science® Google Scholar
38 Cheung M. D., Erman E. N., and Moore K. H., et al.Resident Macrophage Subpopulations Occupy Distinct Microenvironments in the Kidney, JCI Insight. (2022) 7, no. 20, https://doi.org/10.1172/jci.insight.161078.
10.1172/jci.insight.161078
Google Scholar
39 Landis R. C., Quimby K. R., and Greenidge A. R., et al.M1/M2 Macrophages in Diabetic Nephropathy: Nrf2/HO-1 as Therapeutic Targets, Current Pharmaceutical Design. (2018) 24, no. 20, 2241–2249, https://doi.org/10.2174/1381612824666180716163845, 2-s2.0-85055628692.
10.2174/1381612824666180716163845
CAS PubMed Web of Science® Google Scholar
40 Engel J. E. and Chade A. R., Macrophage Polarization in Chronic Kidney Disease: A Balancing Act between Renal Recovery and Decline?, American Journal of Physiology-Renal Physiology. (2019) 317, no. 6, F1409–f1413, https://doi.org/10.1152/ajprenal.00380.2019.
10.1152/ajprenal.00380.2019
CAS PubMed Web of Science® Google Scholar
41 Rosin D. L. and Okusa M. D., Dangers Within: DAMP Responses to Damage and Cell Death in Kidney Disease, Journal of the American Society of Nephrology. (2011) 22, no. 3, 416–425, https://doi.org/10.1681/ASN.2010040430, 2-s2.0-79952339508.
10.1681/ASN.2010040430
CAS PubMed Web of Science® Google Scholar
42 Cao Q., Harris D. C., and Wang Y., Macrophages in Kidney Injury, Inflammation, and Fibrosis, Physiology (Bethesda). (2015) 30, no. 3, 183–194, https://doi.org/10.1152/physiol.00046.2014, 2-s2.0-84929575066.
10.1152/physiol.00046.2014
CAS PubMed Google Scholar
43 Wang X., Chen J., Xu J., Xie J., Harris D. C. H., and Zheng G., The Role of Macrophages in Kidney Fibrosis, Frontiers in Physiology. (2021) 12, https://doi.org/10.3389/fphys.2021.705838.
10.3389/fphys.2021.705838
Google Scholar
44 Murray P. J., Allen J. E., and Biswas S. K., et al.Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines, Immunity. (2014) 41, no. 1, 14–20, https://doi.org/10.1016/j.immuni.2014.06.008, 2-s2.0-84904394690.
10.1016/j.immuni.2014.06.008
CAS PubMed Web of Science® Google Scholar
45 Anders H. J. and Ryu M., Renal Microenvironments and Macrophage Phenotypes Determine Progression or Resolution of Renal Inflammation and Fibrosis, Kidney International. (2011) 80, no. 9, 915–925, https://doi.org/10.1038/ki.2011.217, 2-s2.0-80054728443.
10.1038/ki.2011.217
CAS PubMed Web of Science® Google Scholar
46 Shin N. S., Marlier A., and Xu L., et al.Arginase-1 Is Required for Macrophage-Mediated Renal Tubule Regeneration, Journal of the American Society of Nephrology. (2022) 33, no. 6, 1077–1086, https://doi.org/10.1681/ASN.2021121548.
10.1681/ASN.2021121548
CAS PubMed Web of Science® Google Scholar
47 Wen Y., Yan H. R., Wang B., and Liu B. C., Macrophage Heterogeneity in Kidney Injury and Fibrosis, Frontiers in Immunology. (2021) 12, https://doi.org/10.3389/fimmu.2021.681748.
10.3389/fimmu.2021.681748
Google Scholar
48 Klessens C. Q. F., Zandbergen M., and Wolterbeek R., et al.Macrophages in Diabetic Nephropathy in Patients With Type 2 Diabetes, Nephrology Dialysis Transplantation. (2016) 32, gfw260–1329, https://doi.org/10.1093/ndt/gfw260, 2-s2.0-85026856606.
10.1093/ndt/gfw260
Google Scholar
49 Fan Y., Yi Z., and D’Agati V. D., et al.Comparison of Kidney Transcriptomic Profiles of Early and Advanced Diabetic Nephropathy Reveals Potential New Mechanisms for Disease Progression, Diabetes. (2019) 68, no. 12, 2301–2314, https://doi.org/10.2337/db19-0204.
10.2337/db19-0204
CAS PubMed Web of Science® Google Scholar
50 Zhang X., Yang Y., and Zhao Y., Macrophage Phenotype and Its Relationship With Renal Function in Human Diabetic Nephropathy, PLoS One. (2019) 14, no. 9, https://doi.org/10.1371/journal.pone.0221991, 2-s2.0-85072144985.
10.1371/journal.pone.0221991
Google Scholar
51 Moratal C., Laurain A., and Naïmi M., et al.Regulation of Monocytes/Macrophages by the Renin-Angiotensin System in Diabetic Nephropathy: State of the Art and Results of a Pilot Study, International Journal of Molecular Sciences. (2021) 22, no. 11, https://doi.org/10.3390/ijms22116009.
10.3390/ijms22116009
Google Scholar
52 Wang J., Chen W., Chen S., Yue G., Hu Y., and Xu J., Landscape of Infiltrating Immune Cells and Related Genes in Diabetic Kidney Disease, Clinical and Experimental Nephrology. (2024) 28, no. 3, 181–191, https://doi.org/10.1007/s10157-023-02422-1.
10.1007/s10157-023-02422-1
CAS PubMed Google Scholar
53 Navarro-González J. F., Mora-Fernández C., Muros de Fuentes M., and García-Pérez J., Inflammatory Molecules and Pathways in the Pathogenesis of Diabetic Nephropathy, Nature Reviews Nephrology. (2011) 7, no. 6, 327–340, https://doi.org/10.1038/nrneph.2011.51, 2-s2.0-79957874666.
10.1038/nrneph.2011.51
CAS PubMed Web of Science® Google Scholar
54 Tan A. L., Forbes J. M., and Cooper M. E. A. G. E., RAGE, and ROS in Diabetic Nephropathy, Seminars in Nephrology. (2007) 27, no. 2, 130–143, https://doi.org/10.1016/j.semnephrol.2007.01.006, 2-s2.0-34047248203.
10.1016/j.semnephrol.2007.01.006
CAS PubMed Web of Science® Google Scholar
55 Lee W. J., Liu S. H., and Chiang C. K., et al.Aryl Hydrocarbon Receptor Deficiency Attenuates Oxidative Stress-Related Mesangial Cell Activation and Macrophage Infiltration and Extracellular Matrix Accumulation in Diabetic Nephropathy, Antioxidants & Redox Signaling. (2016) 24, no. 4, 217–231, https://doi.org/10.1089/ars.2015.6310.
10.1089/ars.2015.6310
CAS PubMed Web of Science® Google Scholar
56 Han H. I., Skvarca L. B., Espiritu E. B., Davidson A. J., and Hukriede N. A., The Role of Macrophages during Acute Kidney Injury: Destruction and Repair, Pediatric Nephrology. (2019) 34, no. 4, 561–569, https://doi.org/10.1007/s00467-017-3883-1, 2-s2.0-85041205749.
10.1007/s00467-017-3883-1
PubMed Web of Science® Google Scholar
57 Reiser J., von Gersdorff G., and Loos M., et al.Induction of B7-1 in Podocytes Is Associated With Nephrotic Syndrome, Journal of Clinical Investigation. (2004) 113, no. 10, 1390–1397, https://doi.org/10.1172/JCI20402, 2-s2.0-85047691168.
10.1172/JCI20402
CAS PubMed Web of Science® Google Scholar
58 Wada J. and Makino H., Inflammation and the Pathogenesis of Diabetic Nephropathy, Clinical Science. (2013) 124, no. 3, 139–152, https://doi.org/10.1042/CS20120198, 2-s2.0-84872041647.
10.1042/CS20120198
CAS PubMed Web of Science® Google Scholar
59 Gu L., Hagiwara S., and Fan Q., et al.Role of Receptor for Advanced Glycation End-Products and Signalling Events in Advanced Glycation End-Product-Induced Monocyte Chemoattractant Protein-1 Expression in Differentiated Mouse Podocytes, Nephrology Dialysis Transplantation. (2006) 21, no. 2, 299–313, https://doi.org/10.1093/ndt/gfi210, 2-s2.0-31544463531.
10.1093/ndt/gfi210
CAS PubMed Web of Science® Google Scholar
60 Jin Q., Liu T., and Qiao Y., et al.Oxidative Stress and Inflammation in Diabetic Nephropathy: Role of Polyphenols, Frontiers in Immunology. (2023) 14, https://doi.org/10.3389/fimmu.2023.1185317.
10.3389/fimmu.2023.1185317
Google Scholar
61 D’Arcy M. S., Cell Death: A Review of the Major Forms of Apoptosis, Necrosis and Autophagy, Cell Biology International. (2019) 43, no. 6, 582–592, https://doi.org/10.1002/cbin.11137, 2-s2.0-85066406374.
10.1002/cbin.11137
PubMed Web of Science® Google Scholar
62 Yu J., Wu H., Liu Z. Y., Zhu Q., Shan C., and Zhang K. Q., Advanced Glycation End Products Induce the Apoptosis of and Inflammation in Mouse Podocytes through CXCL9-Mediated JAK2/STAT3 Pathway Activation, International Journal of Molecular Medicine. (2017) 40, no. 4, 1185–1193, https://doi.org/10.3892/ijmm.2017.3098, 2-s2.0-85029144454.
10.3892/ijmm.2017.3098
CAS PubMed Web of Science® Google Scholar
63 Parwani K. and Mandal P., Role of Advanced Glycation End Products and Insulin Resistance in Diabetic Nephropathy, Archives of Physiology and Biochemistry. (2023) 129, no. 1, 95–107, https://doi.org/10.1080/13813455.2020.1797106.
10.1080/13813455.2020.1797106
CAS PubMed Web of Science® Google Scholar
64 Chen A., Feng Y., and Lai H., et al.Soluble RARRES1 Induces Podocyte Apoptosis to Promote Glomerular Disease Progression, Journal of Clinical Investigation. (2020) 130, no. 10, 5523–5535, https://doi.org/10.1172/JCI140155.
10.1172/JCI140155
CAS PubMed Google Scholar
65 Fan Y., Yang Q., and Yang Y., et al.Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation, International Journal of Biological Sciences. (2019) 15, no. 3, 701–713, https://doi.org/10.7150/ijbs.29323, 2-s2.0-85061399056.
10.7150/ijbs.29323
CAS PubMed Google Scholar
66 Wang F., Li R., Zhao L., Ma S., and Qin G., Resveratrol Ameliorates Renal Damage by Inhibiting Oxidative Stress-Mediated Apoptosis of Podocytes in Diabetic Nephropathy, European Journal of Pharmacology. (2020) 885, https://doi.org/10.1016/j.ejphar.2020.173387.
10.1016/j.ejphar.2020.173387
Google Scholar
67 Guo Y., Song Z., and Zhou M., et al.Infiltrating Macrophages in Diabetic Nephropathy Promote Podocytes Apoptosis via TNF-α-ROS-p38MAPK Pathway, Oncotarget. (2017) 8, no. 32, 53276–53287, https://doi.org/10.18632/oncotarget.18394.
10.18632/oncotarget.18394
PubMed Google Scholar
68 Han J., Pang X., Zhang Y., Peng Z., Shi X., and Xing Y., Hirudin Protects Against Kidney Damage in Streptozotocin-Induced Diabetic Nephropathy Rats by Inhibiting Inflammation via P38 MAPK/NF-κB Pathway, Drug Design, Development and Therapy. (2020) 14, 3223–3234, https://doi.org/10.2147/DDDT.S257613.
10.2147/DDDT.S257613
CAS PubMed Web of Science® Google Scholar
69 Wan J., Liu D., Pan S., Zhou S., and Liu Z., NLRP3-Mediated Pyroptosis in Diabetic Nephropathy, Frontiers in Pharmacology. (2022) 13, https://doi.org/10.3389/fphar.2022.998574.
10.3389/fphar.2022.998574
Google Scholar
70 Zuo Y., Chen L., and Gu H., et al.GSDMD-Mediated Pyroptosis: A Critical Mechanism of Diabetic Nephropathy, Expert Reviews in Molecular Medicine. (2021) 23, https://doi.org/10.1017/erm.2021.27.
10.1017/erm.2021.27
PubMed Google Scholar
71 Cheng Q., Pan J., and Zhou Z. L., et al.Caspase-11/4 and Gasdermin D-Mediated Pyroptosis Contributes to Podocyte Injury in Mouse Diabetic Nephropathy, Acta Pharmacologica Sinica. (2021) 42, no. 6, 954–963, https://doi.org/10.1038/s41401-020-00525-z.
10.1038/s41401-020-00525-z
CAS PubMed Web of Science® Google Scholar
72 Wang G., Jin S., and Huang W., et al.LPS-Induced Macrophage HMGB1-Loaded Extracellular Vesicles Trigger Hepatocyte Pyroptosis by Activating the NLRP3 Inflammasome, Cell Death Discovery. (2021) 7, no. 1, https://doi.org/10.1038/s41420-021-00729-0.
10.1038/s41420-021-00729-0
Google Scholar
73 Voet S., Mc Guire C., and Hagemeyer N., et al.A20 Critically Controls Microglia Activation and Inhibits Inflammasome-Dependent Neuroinflammation, Nature Communications. (2018) 9, no. 1, https://doi.org/10.1038/s41467-018-04376-5, 2-s2.0-85047762349.
10.1038/s41467-018-04376-5
Google Scholar
74 Su P. P., Liu D. W., Zhou S. J., Chen H., Wu X. M., and Liu Z. S., Down-Regulation of Risa Improves Podocyte Injury by Enhancing Autophagy in Diabetic Nephropathy, Military Medical Research. (2022) 9, no. 1, https://doi.org/10.1186/s40779-022-00385-0.
10.1186/s40779-022-00385-0
Google Scholar
75 Parmar U. M., Jalgaonkar M. P., Kulkarni Y. A., and Oza M. J., Autophagy-Nutrient Sensing Pathways in Diabetic Complications, Pharmacological Research. (2022) 184, https://doi.org/10.1016/j.phrs.2022.106408.
10.1016/j.phrs.2022.106408
PubMed Google Scholar
76 Yang D., Livingston M. J., and Liu Z., et al.Autophagy in Diabetic Kidney Disease: Regulation, Pathological Role and Therapeutic Potential, Cellular and Molecular Life Sciences. (2018) 75, no. 4, 669–688, https://doi.org/10.1007/s00018-017-2639-1, 2-s2.0-85028855063.
10.1007/s00018-017-2639-1
CAS PubMed Web of Science® Google Scholar
77 Liu Y., Li X., and Zhao M., et al.Macrophage-Derived Exosomes Promote Activation of NLRP3 Inflammasome and Autophagy Deficiency of Mesangial Cells in Diabetic Nephropathy, Life Science Part 1 Physiology & Pharmacology. (2023) 330, https://doi.org/10.1016/j.lfs.2023.121991.
10.1016/j.lfs.2023.121991
Google Scholar
78 Zhao J., Chen J., Zhu W., Qi X. M., and Wu Y. G., Exosomal miR-7002-5p Derived from Highglucose-Induced Macrophages Suppresses Autophagy in Tubular Epithelial Cells by Targeting Atg9b, The FASEB Journal. (2022) 36, no. 9, https://doi.org/10.1096/fj.202200550RR.
10.1096/fj.202200550RR
Google Scholar
79 Wang J., Zhou J. Y., Kho D., ReinersJ. J.Jr., and Wu G. S., Role for DUSP1 (dual-Specificity Protein Phosphatase 1) in the Regulation of Autophagy, Autophagy. (2016) 12, no. 10, 1791–1803, https://doi.org/10.1080/15548627.2016.1203483, 2-s2.0-84983504594.
10.1080/15548627.2016.1203483
CAS PubMed Web of Science® Google Scholar
80 Liu X. Q., Jiang L., and Li Y. Y., et al.Wogonin Protects Glomerular Podocytes by Targeting Bcl-2-Mediated Autophagy and Apoptosis in Diabetic Kidney Disease, Acta Pharmacologica Sinica. (2022) 43, no. 1, 96–110, https://doi.org/10.1038/s41401-021-00721-5.
10.1038/s41401-021-00721-5
CAS PubMed Web of Science® Google Scholar
81 Erekat N. S., Programmed Cell Death in Diabetic Nephropathy: A Review of Apoptosis, Autophagy, and Necroptosis, Medical Science Monitor. (2022) 28, https://doi.org/10.12659/MSM.937766.
10.12659/MSM.937766
Google Scholar
82 Xu Y., Gao H., and Hu Y., et al.High Glucose-Induced Apoptosis and Necroptosis in Podocytes Is Regulated by UCHL1 via RIPK1/RIPK3 Pathway, Experimental Cell Research. (2019) 382, no. 2, https://doi.org/10.1016/j.yexcr.2019.06.008, 2-s2.0-85068061992.
10.1016/j.yexcr.2019.06.008
Google Scholar
83 Hu H., Li M., Chen B., Guo C., and Yang N., Activation of Necroptosis Pathway in Podocyte Contributes to the Pathogenesis of Focal Segmental Glomerular Sclerosis, Clinical and Experimental Nephrology. (2022) 26, no. 11, 1055–1066, https://doi.org/10.1007/s10157-022-02258-1.
10.1007/s10157-022-02258-1
CAS PubMed Google Scholar
84 Meng X. M., Ren G. L., and Gao L., et al.NADPH oxidase 4 Promotes Cisplatin-Induced Acute Kidney Injury via ROS-Mediated Programmed Cell Death and Inflammation, Laboratory Investigation. (2018) 98, no. 1, 63–78, https://doi.org/10.1038/labinvest.2017.120, 2-s2.0-85042767665.
10.1038/labinvest.2017.120
CAS PubMed Google Scholar
85 Guo M., Chen Q., and Huang Y., et al.High Glucose-Induced Kidney Injury via Activation of Necroptosis in Diabetic Kidney Disease, Oxidative Medicine and Cellular Longevity. (2023) 2023, 14.
10.1155/2023/2713864
Google Scholar
86 Xu D., Qu X., and Tian Y., et al.Macrophage Notch1 Inhibits TAK1 Function and RIPK3-Mediated Hepatocyte Necroptosis through Activation of β-Catenin Signaling in Liver Ischemia and Reperfusion Injury, Cell Communication and Signaling. (2022) 20, no. 1, https://doi.org/10.1186/s12964-022-00901-8.
10.1186/s12964-022-00901-8
Google Scholar
87 Cui C., Wang F., Zheng Y., Wei H., and Peng J., From Birth to Death: The Hardworking Life of Paneth Cell in the Small Intestine, Frontiers in Immunology. (2023) 14, https://doi.org/10.3389/fimmu.2023.1122258.
10.3389/fimmu.2023.1122258
Google Scholar
88 Ma T., Li X., and Zhu Y., et al.Excessive Activation of Notch Signaling in Macrophages Promote Kidney Inflammation, Fibrosis, and Necroptosis, Frontiers in Immunology. (2022) 13, https://doi.org/10.3389/fimmu.2022.835879.
10.3389/fimmu.2022.835879
Google Scholar
89 Wu W. Y., Wang Z. X., and Li T. S., et al.SSBP1 Drives High Fructose-Induced Glomerular Podocyte Ferroptosis via Activating DNA-PK/p53 Pathway, Redox Biology. (2022) 52, https://doi.org/10.1016/j.redox.2022.102303.
10.1016/j.redox.2022.102303
Google Scholar
90 He X., Yang L., and Wang M., et al.Targeting Ferroptosis Attenuates Podocytes Injury and Delays Tubulointerstitial Fibrosis in Focal Segmental Glomerulosclerosis, Biochemical and Biophysical Research Communications. (2023) 678, 11–16, https://doi.org/10.1016/j.bbrc.2023.08.029.
10.1016/j.bbrc.2023.08.029
CAS PubMed Web of Science® Google Scholar
91 Chen J., Fu C. Y., and Shen G., et al.Macrophages Induce Cardiomyocyte Ferroptosis via Mitochondrial Transfer, Free Radical Biology and Medicine. (2022) 190, 1–14, https://doi.org/10.1016/j.freeradbiomed.2022.07.015.
10.1016/j.freeradbiomed.2022.07.015
CAS PubMed Web of Science® Google Scholar
92 Gu Y. Y., Lu F. H., and Huang X. R., et al.Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease, Frontiers in Pharmacology. (2021) 11, https://doi.org/10.3389/fphar.2020.583528.
10.3389/fphar.2020.583528
Google Scholar
93 Liang M., Zhu X., and Zhang D., et al.Yi-Shen-Hua-Shi Granules Inhibit Diabetic Nephropathy by Ameliorating Podocyte Injury Induced by Macrophage-Derived Exosomes, Frontiers in Pharmacology. (2022) 13, https://doi.org/10.3389/fphar.2022.962606.
10.3389/fphar.2022.962606
Google Scholar
94 Zhuang Y., Zheng H., Yang Y., and Ni H., GABA Alleviates High Glucose-Induced Podocyte Injury through Dynamically Altering the Expression of Macrophage M1/M2-Derived Exosomal miR-21a-5p/miR-25-3p, Biochemical and Biophysical Research Communications. (2022) 618, 38–45, https://doi.org/10.1016/j.bbrc.2022.06.019.
10.1016/j.bbrc.2022.06.019
CAS PubMed Web of Science® Google Scholar
95 Wang Z., Sun W., Li R., and Liu Y., MiRNA-93-5p in Exosomes Derived from M2 Macrophages Improves Lipopolysaccharide-Induced Podocyte Apoptosis by Targeting Toll-Like Receptor 4, Bioengineered. (2022) 13, no. 3, 7683–7696, https://doi.org/10.1080/21655979.2021.2023794.
10.1080/21655979.2021.2023794
CAS PubMed Web of Science® Google Scholar
96 Guiteras R., Sola A., Flaquer M., Manonelles A., Hotter G., and Cruzado J. M., Exploring Macrophage Cell Therapy on Diabetic Kidney Disease, Journal of Cellular and Molecular Medicine. (2019) 23, no. 2, 841–851, https://doi.org/10.1111/jcmm.13983, 2-s2.0-85056207222.
10.1111/jcmm.13983
CAS PubMed Web of Science® Google Scholar
97 Ma Y., Chen Y., Xu H., and Du N., The Influence of Angiopoietin-Like Protein 3 on Macrophages Polarization and Its Effect on the Podocyte EMT in Diabetic Nephropathy, Frontiers in Immunology. (2023) 14, https://doi.org/10.3389/fimmu.2023.1228399.
10.3389/fimmu.2023.1228399
Google Scholar
98 Wang X., Yao B., and Wang Y., et al.Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy, Diabetes. (2017) 66, no. 2, 494–504, https://doi.org/10.2337/db16-0773, 2-s2.0-85011708582.
10.2337/db16-0773
CAS PubMed Google Scholar
99 Zhang X. L., Guo Y. F., Song Z. X., and Zhou M., Vitamin D Prevents Podocyte Injury via Regulation of Macrophage M1/M2 Phenotype in Diabetic Nephropathy Rats, Endocrinology. (2014) 155, no. 12, 4939–4950, https://doi.org/10.1210/en.2014-1020, 2-s2.0-84914101858.
10.1210/en.2014-1020
CAS PubMed Web of Science® Google Scholar
100 Jiandong L., Yang Y., and Peng J., et al.Trichosanthes kirilowii Lectin Ameliorates Streptozocin-Induced Kidney Injury via Modulation of the Balance between M1/M2 Phenotype Macrophage, Biomedicine & Pharmacotherapy. (2019) 109, 93–102, https://doi.org/10.1016/j.biopha.2018.10.060, 2-s2.0-85055905692.
10.1016/j.biopha.2018.10.060
CAS PubMed Web of Science® Google Scholar
101 Liao H., Li Y., and Zhang X., et al.Protective Effects of Thalidomide on High-Glucose-Induced Podocyte Injury through In Vitro Modulation of Macrophage M1/M2 Differentiation, Journal of Immunological Research. (2020) 2020, 1–14.
10.1155/2020/8263598
Google Scholar
102 Liu J., Zhang Y., and Sheng H., et al.Hyperoside Suppresses Renal Inflammation by Regulating Macrophage Polarization in Mice With Type 2 Diabetes Mellitus, Frontiers in Immunology. (2021) 12, https://doi.org/10.3389/fimmu.2021.733808.
10.3389/fimmu.2021.733808
Google Scholar
103 Yang H., Xie T., and Li D., et al.Tim-3 Aggravates Podocyte Injury in Diabetic Nephropathy by Promoting Macrophage Activation via the NF-κB/TNF-α Pathway, Molecular Metabolism. (2019) 23, 24–36, https://doi.org/10.1016/j.molmet.2019.02.007, 2-s2.0-85062668821.
10.1016/j.molmet.2019.02.007
CAS PubMed Web of Science® Google Scholar
104 Wang Z., Wei M., and Wang M., et al.Inhibition of Macrophage Migration Inhibitory Factor Reduces Diabetic Nephropathy in Type II Diabetes Mice, Inflammation. (2014) 37, no. 6, 2020–2029, https://doi.org/10.1007/s10753-014-9934-x, 2-s2.0-84937558875.
10.1007/s10753-014-9934-x
CAS PubMed Web of Science® Google Scholar
105 Miyamoto S., Shikata K., and Miyasaka K., et al.Cholecystokinin Plays a Novel Protective Role in Diabetic Kidney through Anti-Inflammatory Actions on Macrophage: Anti-Inflammatory Effect of Cholecystokinin, Diabetes. (2012) 61, no. 4, 897–907.
10.2337/db11-0402
CAS PubMed Web of Science® Google Scholar

All articles

Cross Talk Between Macrophages and Podocytes in Diabetic Nephropathy: Potential Mechanisms and Novel Therapeutics

Abstract

1. Introduction

2. Podocytes in DN

3. Macrophages in DN

3.1. Origins and Phenotypes of Macrophages

3.2. Pathogenic Roles of Macrophages in DN

4. Cross Talk Between Podocytes and Macrophages in DN

4.1. Effects of Podocytes on Macrophage Activation