3.1. Antioxidant Activity

Oxidative stress is associated with diminished antioxidant enzyme levels and the activation of inflammatory pathways. Oxidative stress and chronic inflammation jointly contribute to myriad molecular and cellular changes, encompassing genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence, and stem cell loss [46]. Damage to podocyte and the activation of parietal epithelial cells (PECs) are critical in the progression of kidney injury. During glomerular injury, mediators including inflammatory cytokines, complement, angiotensin II, and metabolites can induce damage to podocytes and activate intracellular pathways such as oxidative stress and Notch signaling. Moreover, PECs contribute to fibrosis, leading to rapid and progressive glomerulonephritis/crescent glomerulonephritis (RPGN/CGN). During the crescent formation, the activated PECs invade the glomerular urinary space, causing an irreversible distortion of the glomerular structure and blocking the urinary space [47, 48]. Numerous evidence indicate that oxidative stress is one of the major risk factors for the onset of diabetic kidney [49, 50]. Ginger is regarded as an antioxidant treasure owing to its ability to scavenge reactive oxygen species (ROS). High-performance liquid chromatography (HPLC) results revealed the presence of rosmarinic acid, caffeic acid, p-hydroxybenzoic acid, luteolin, and quercetin in ginger water extract, contributing to potential activity against free radicals [51]. A study aiming to examine the effect of 1,8-cineole (eucalyptol) on gentamicin (GM)-induced renal toxicity found that 1,8-cineole decreased the expressions of inducible nitric oxide synthase (iNOS) and 8-hydroxy-2 deoxyguanosine (8-OHdG), while it caused increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) [15]. In renal I/R models, geraniol may attenuate oxidation by inhibiting the Toll-like receptor 2,4/myeloid differentiation factor 88/nuclear factor kappa-B (TLR2,4/MYD88/NF-κB) pathway [17]. In lipopolysaccharide (LPS)-induced mouse accelerated and severe lupus nephritis (ASLN) model, researchers found that citral can enhance the activation of Nrf2 antioxidant signaling, and thereby exerting renoprotective effects [18]. Another study on the protective effect of linalool against doxorubicin (DOX)-induced renal injury found that linalool supplementation led to a significant decrease in malondialdehyde (MDA) and increases in superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels as well [21]. Ginger extract exhibits notable renal protective activity by reducing MDA and protein carbonyl contents, while increases GSH, SOD, and CAT in the diabetic rat model induced by intraperitoneal injection of streptozotocin (STZ) [52]. Another experiment using STZ-induced diabetic rat model also found that 6-gingerol reduced lipid parameters, inflammation, and oxidative stress in diabetic rats, thereby inhibiting the renal damage [36]. Experiments conducted on db/db mouse models and glucose-treated human proximal tubular cell line (HK-2) cells revealed that Zingerone reduced MDA levels, increased GSH content, and significantly decreased the expression of NADPH oxidase 4 (NOX4) in vivo and in vitro, protecting against diabetic nephropathy (DN) [41]. Studies on combined osteoporosis (CMO) model rats also revealed that ginger protected the kidneys by reducing advanced oxidation protein products (AOPP), lipid peroxidation, SOD, CAT, and GSH peroxidase activities [51]. In an animal experiment focusing on both acute and chronic renal failure, using 30-min ischemia followed by 24-h reperfusion model, and adenine feeding for 8-week model, researchers found normalized renal SOD levels in both disease models after ginger treatment, confirming that ginger has the effect of reducing lipid peroxidation [53]. In the kidney of the alcohol-treated rat model, antioxidant enzyme activity and GSH level were significantly decreased (p < 0.001), while MDA level was increased. However, supplementing ginger extract can reverse this process and restore the antioxidant state to normal [54]. Therefore, ginger is often used in the treatment of anti-AKI as an effective remedy against nephrotoxic substances, medications, alcohol, and other detrimental factors. Ginger’s radical scavenging properties are well suited for metal chelation [55]. 6-gingerol prevented free radicals from attacking the biofilm caused by metals, and thus protecting the liver and kidney of Sprague–Dawley (SD) rats against the acute poisoning with mercury chloride [37]. Ginger can protect cell apoptosis induced by cadmium-stimulated ROS production by upregulating glutathione S-transferase (GST) gene expression [56]. Zingerone prevented lead-induced nephrotoxicity by regulating oxidative damage in Wistar rats [31]. Zingerone also has nephroprotective effects in the cisplatin rat model by significantly decreasing the levels of MDA and significantly retaining the enzyme activity of CAT and glutathione peroxidase (GPX) in kidney tissue [42]. In a streptozotocin/high-fat diet (STZ/HFD)-induced type 2 diabetic Wistar rat model, zingerone markedly abrogated ROS level, suggesting the efficacy of zingerone in the treatment of DN by antioxidant effect [43]. 6-shogaol improves renal dysfunction and tubular damage by regulating the expression of prooxidant enzymes and antioxidative enzymes in model of cisplatin induction [39]. The oxidative stress and DNA damage induced by vancomycin (VCM) in the animal model were significantly reduced after ginger treatment [57]. In contrast-induced nephropathy (CIN), the contrast agent causes decreased SOD activity and GSH levels in the kidney, but ginger extract has protective effects by restoring the concentrations of these oxidative stress markers [58]. GM induces renal damage by overproduction of ROS and inflammation in proximal tubular cells. Gingerol can promote nephroprotective effect by improving the levels of GSH and SOD activity in the kidneys of GM-mediated male Wistar rats [38]. The protective effect of ginger antioxidants on the kidneys has also been demonstrated in clinical trials. The findings suggested that ginger reduced blood glucose levels, improved insulin sensitivity, and decreased serum urea levels in hemodialysis patients with diabetes [59]. Moreover, a randomized controlled trial proved the beneficial effect of ginger on blood lipids and lipoproteins in peritoneal dialysis patients [60]. These studies demonstrated that ginger can exert a renal protective effect by inhibiting oxidative stress. Overall, ginger bioactive compounds show renal protective activity by inhibiting oxidative stress, resisting metals, poisons, and other stimuli.

3.2. Anti-Inflammatory Activity

The involvement of inflammatory mediators induced the development and progression of renal disease. Inflammation is a key risk factor for the progression of CKD [61]. Data from the CANTOS trial suggest that anti-inflammatory treatment in CKD patients reduces major adverse cardiovascular events [62]. The altered effect of uremia on the immune system has been described as uremia inflammation [63], which is characterized by the abnormal activation of the innate immune system, especially for monocytes. This immune activation induces systemic inflammation by increasing the synthesis of proinflammatory cytokines [64]. Moreover, inflammation is a significant component of other diseases that are independent risk factors for CKD, such as the obese [65].

Studies demonstrated that the major components of ginger can exert anti-inflammatory effects by inhibiting the production of inflammatory mediators, including prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and NF-κB [66]. They also inhibit the generation of cyclooxygenase-1 (COX-1) and COX-2 [67]. In the animal model studies of DN, ginger alleviated oxidative stress, inflammation, and apoptosis induced by hyperglycemia [52]. Ginger inhibited fructose-stimulated monocyte chemoactant protein-1 (MCP-1) and chemokine (C-C motif) receptor, and downregulated the overexpression of TNF-α, interleukin-6 (IL-6), transforming growth factor-β1 (TGF-β1), plasminogen activator inhibitor-1 (PAI-1), CD68, and F4/80 (two important macrophage accumulation markers) [68]. Essential oil from ginger exerts anti-inflammatory effects by inhibiting altered levels of renal function markers and cytokines expression IL-6, interleukin-10 (IL-10), and TNF-α in cadmium-treated rats [69]. A study on the effects of zerumbone in rats with streptozotocin-induced DN found that zerumbone can inhibit macrophage infiltration via reducing p38-mediated inflammatory response, and thus reducing levels of interleukin-1 (IL-1), IL-6 and TNF-α [20]. In the model of cisplatin-induced AKI, 6-shogaol reduced the levels of TNF-α and IL-6 in serum and kidney, suggesting that 6-shogaol protects the kidney by retarding systemic and renal inflammation [39]. Moreover, the chemokines MCP-1 and chemokine C-C motif ligand 5 (CCL5) play vital roles in recruiting macrophages and T cells into the tissue [70]. This study also found that 6-shogaol reduced the expression of MCP-1 and CCL5 and significantly inhibited cisplatin-induced abnormal infiltration of macrophages and CD4+T cells into the kidney. Compared to 6-gingerol, 6-shogaol reduced more nitric oxide (NO) synthesis, and inhibited the release of arachidonic acid more effectively [71]. A study confirmed the renal protective effects of 6-shogaol in vitro and in vivo, respectively. In vivo, compared with mice receiving renal IR, studies found that 6-shogaol was protective against ischemic AKI by attenuating NF-κB activation, inducing heme oxygenase 1 (HO-1) expression, reducing pro-inflammatory cytokines, and chemokines’ synthesis as well as neutrophil infiltration. In vitro studies, when the HK-2 cells and mouse kidney proximal tubule cells were pretreated with 6-shogaol, nuclear p65 translocation, IκBα degradation, IκBα phosphorylation, and an abnormal increase in IKKα/β were all significantly attenuated. It shows that 6-shogaol can attenuate the NFκB activity induced by TNF-α, and the synthesis of pro-inflammatory messenger ribonucleoic acids induced by TNF-α or LPS in cultured proximal tubules [40].

Impairment of immune homeostasis is a key factor in the development of autoimmune diseases. ADA, the degrading enzyme of adenosine (the immunosuppressive signal), serves as the key checkpoint in regulating extracellular adenosine levels [72]. The adenosine pathway plays a crucial role in regulating the inflammatory response and protecting against kidney injury [73]. ADA activity is altered in many autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and ulcerative colitis (UC). ADA is also implicated in the progression of various renal diseases [74]. In the study of the protective effect of ginger essential oil components toward cadmium-induced nephrotoxicity in rats, treatment with ginger essential oil prevented the increased ADA activity induced by cadmium and increased the extracellular adenosine levels, leading to aprotective effect to the kidney [69].

Moreover, the mechanism of action of zingerone in AKI has received considerable attentions. Studies found that zingerone can inhibit the levels of inflammatory factors TNF-α, IL-6, and IL-1β. It also inhibited the expression of Toll-like receptor 4 (TLR4), MyD88, TIR-domain-containing adaptor inducing interferon-β (TRIF), and NF-κB activation, indicating that zingerone can inhibit lps-induced AKI by inhibiting the TLR4/NF-κB signaling pathway [44]. Another study found that zingerone inhibited the activation of NF-kB after cecal ligation puncture (CLP), indicating that the upregulation of TNF-α and IL-6 levels were at least partially affected by zingerone [45]. Simultaneously, they found that zingerone reduced the release of high-mobility group protein 1 (HMGB1) in vitro experiments, and HMGB1 is a late mediator in the severe vascular inflammatory response in bacterial LPS-activated human endothelial cells. This inhibition of HMGB1-mediated inflammatory response [75]. In the study investigating zingerone’s inhibition of age-related inflammation, COX-2 and iNOS were upregulated with age through NF-kB activation and inhibitor of kappa B kinase/mitogen-activated protein kinase (IKK/MAPK) signaling. Zingerone exerted renal protective effects by inhibiting the expression of these key proinflammatory genes and transcription factors [76]. In another study, cisplatin induced the inflammatory response in female Wistar rats by increasing the levels of TNF-α, IL-1β, IL-6, interleukin-33 (IL-33), and NF-κB, while zingerone significantly reduced these indices, and increased renal aquaporins (AQP1) protein levels. However, the AQP1 proteins caused by CP may be attributed primarily to structural damage in the proximal nephron [77].

Due to its outstanding anti-inflammatory effects, ginger can be employed in the clinical treatment of kidney function [66]. In a clinical study investigating the effect of ginger on serum glucose, advanced glycation end-products (AGEs), and inflammation in peritoneal dialysis patients, the concentrations of serum carboxymethyl lysine and pentoxide (serum AGE concentrations) did not significantly increase in the ginger-treated group. The concentrations of soluble intercellular adhesion molecule type 1 (sICAM-1) and soluble vascular cell adhesion molecule type 1 (sVCAM-1) (vascular inflammatory markers) also did not rise abnormally compared with the placebo group, confirming the effect of ginger on glucose metabolites and inflammatory indicators in peritoneal dialysis patients [78]. Additionally, it exhibits antinociceptive effects induced by acetic acid. Using an allyl isothiocyanate (AITC)-induced rat model, researchers discovered that percutaneous administration of ginger extract ointment exhibits effective analgesic and anti-inflammatory activity in rat hindlimb plantar fasciitis [79]. The effects of ginger have been demonstrated to be comparable to nonsteroidal anti-inflammatory drugs (NSAIDs) but without adverse effects on the gastric mucosa [1].

3.3. Reduction of Endothelial Dysfunction

Endothelial cells are key cellular components of blood vessels that act as a selective penetration barrier between blood and tissue. Endothelial cell injury is closely related to thrombosis, hypertension, renal failure, and atherosclerosis, and it may also be the cause of accelerated atherosclerosis in patients with chronic renal failure [80]. In patients with CKD, persistent endothelial damage of the renal medullary capillary system and concomitant vascular thinning are considered as the core process of progressive renal damage [81]. Traditional risk factors cannot explain the high prevalence and incidence of cardiovascular disease in CKD. Thus, studies of nontraditional risk factors such as endothelial dysfunction, oxidative stress, or insulin resistance are rapidly increasing [80, 82].

Ginger bioactive compounds may protect the kidney function by alleviating endothelial dysfunction. 6-shogaol and 6-gingerol can regulate endothelial dysfunction and NO synthesis, and the mechanism is mainly related to endothelial cell apoptosis, abnormal lipid transport, and plaque rupture. Moreover, the occurrence of CKD after AKI caused by the hypoxic scarring and capillary loss was also proposed [52]. The main mechanisms of endothelial dysfunction that initiate and maintain AKI are attributed to endothelium-dependent vasodilation, changes in capillary barrier function, and modulation of proinflammatory and procoagulant pathways [83]. In two experimental models that endothelial dysfunction leads to injury of nonendothelial cells within the basin of a feeding capillary, a study found that injecting endothelial cells could improve endothelial dysfunction in ischemic ARF. This suggests that cell-based therapy can improve AKI by enhancing endothelial function and repairing microvascular damage [84]. It was found that 6-gingerol attenuates high-glucose-induced Human umbilical vein endothelial cells’ (HUVEC) damage, by activating the phosphoinositide 3 kinase–protein kinase B–endothelial nitric oxide synthase (PI3K-AKT-eNOS) signaling pathway [85]. Another study found that 6-gingerol upgraded phosphorylated endothelial nitric oxide synthase (eNOS) protein but decreased vascular cell adhesion molecule 1 (VCAM-1) and TNF-α protein in HUVEC [86].

3.4. Inhibition of Apoptosis and Necroptosis

Cell apoptosis is a normal cell death process driven by multiple physiological and pathological stimuli [87]. As a tumor suppressor protein, p53 can trigger cell cycle arrest, apoptosis, and/or cell death depending on the severity of DNA damage [88]. B-cell lymphoma-2-associated X (Bax) proteins also promote apoptosis and are thought to be one of the main targets of the p53 tumor suppressor. This apoptosis activation involves the transcription-independent and Bax-dependent release of cytochrome c, permeabilizing and destroying the mitochondrial membrane and activating the caspases [89]. Caspase-3 is a key mediator of apoptosis in mammalian cells, initiating the apoptotic process through the activation of other caspase enzymes [90]. In the study aiming to elucidate the ameliorative effects of the monoterpene linalool against GM-mediated AKI in rats, researchers found that linalool repressed apoptosis, accompanied by a marked downregulation of Bax and caspase-3 expression, concurrent with the upregulation of B-cell lymphoma-2 (Bcl2) expression [19]. In the mechanistic study of VCM-induced kidney injury, it was found that VCM directly triggered mitochondrial membrane potential depolarization, resulting in released cytochrome c and activated caspase-9. Subsequently, caspase-9 activated caspase-3, leading to apoptosis. Treatment with zingerone markedly inhibited the expression of Bax, caspase-3, and p53 protein level, and so it can protect the kidney by inhibiting apoptosis [57]. Oxidative stress can promote tubular cell apoptosis, and this symptom is a marker of cisplatin-induced AKI [91]. Treatment with 6-shogaol was found to reduce tubular apoptosis in a mouse ischemic AKI model [39]. Further studies revealed that necroptosis also played an important role in cisplatin-induced AKI in addition to apoptosis [92]. Studies have reported that the expressions of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and p-mixed lineage kinase domain-like (p-MLKL) in the kidney were elevated after cisplatin-induced kidney injury [93]. During necroptosis, RIPK1 interacts with RIPK3 to form a heterodimeric complex that promotes its oligomerization through phosphorylation of mixed lineage kinase domain-like (MLKL). The oligomeric form of MLKL translocates to the plasma membrane, resulting in membrane rupture. Thus, inhibition of RIPK1 activity ameliorated tubular cell necrosis and kidney injury in cisplatin-induced mice. Significant attenuation of both RIPK1 and detected renal injury was observed after treatment with 6-shogaol. These evidences suggest that 6-shogaol suppresses two main types of tubular cell death in cisplatin-induced renal injury [39].

3.5. Others

In recent years, there have been new discoveries about the mechanism of ginger’s protection on the kidney. The effect of ginger bioactive compounds in reducing fibrosis holds significant importance in the kidney. Chronic renal fibrosis is the final result of glomerular, vascular, and interstitial inflammation, leading the kidney into the end-stage renal disease (ESRD) stage [94, 95]. If the injury state continues, it will cause glomerulosclerosis, tubular atrophy, interstitial fibrosis, and capillary sclerosis [96]. Fibrosis can disrupt glomerular and tubular structures and overactivate the expression of TGF-β1 (the main profibrotic cytokine), thus inducing the accumulation of inflammatory cells and fibroblasts in the area of injury. Excessive proliferation of fibroblasts and myofibroblasts is one of the hallmarks of fibrosis, and TGF-β1 stimulates these cells to produce more cytokines, and thus enhances extracellular matrix (ECM) synthesis and inhibits ECM degradation, ultimately causing the accumulation of ECM [97]. A study investigated the inhibition of 1,8-cineole on tubular epithelial cell disjunction and tubulointerstitial fibrosis stimulated by glucose, which found that 1,8-cineole attenuated the induction of Snail1, β-catenin, and integrin-linked kinase 1 (ILK1). This can reverse tissue levels of E-cadherin, N-cadherin, and P-cadherin, and the collagen fiber deposition through blocking ILK1-dependent transcriptional interaction of Snail1/β-catenin in diabetic kidneys [16]. Major profibrotic factors consist of fibroblast growth factor (FGF), connective tissue growth factor (CTGF), and insulin-like growth factor-1 (IGF-1) [98]. IGF1 is considered to be a mitogenic factor that promotes ECM accumulation in various cell types (including fibroblasts) [99], thereby increasing collagen synthesis [100]. On the other hand, fibrosis-alleviating factors such as hepatocyte growth factor (HGF) and bone morphogenic protein-7 (BMP-7) also play important roles in renal fibrosis. HGF was inversely associated with TGF-β1 mRNA expression, indicating that HGF can directly antagonize the profibrotic effect of TGF-β1 [101, 102]. Studies have found that elevating the expression of IGF-1 and HGF depletion contributed to fibrosis in the cisplatin rat model. As one of the main active components in ginger, 10-dehydrogingerdione (10-DHGD) was found to attenuate renal tissue fibrosis by inhibiting TGF-β1 and IGF-1 expressions and increasing HGF expression [103]. The global regulation of these growth regulatory molecules by 10-DHGD can protect renal tissue to reduce fibrosis and promote cellular repair, thus confirming the protective effect of ginger on renal fibrosis.

Additionally, ginger bioactive compounds have received considerable attentions for their roles in regulating autophagy [104]. Autophagy is an intracellular degradation system that maintains cellular homeostasis [105]. Autophagy plays a key role in various diseases, for example, kidney disease [106]. Due to observing the number of MAP1LC3B/LC3B spots in GFP-LC3 transgenic mice, researchers identified a rapid increase in autophagy in response to acute pathological stimuli (such as ischemia/reperfusion injury, urinary tract obstruction, and the toxic side effects of cisplatin and cyclosporin A). This indicates that autophagy protects the kidney from tubular injury and secondary fibrosis [107–109]. A study on the protective effect of zingerone against sodium arsenite (SA) inducing nephrotoxicity found that the administration of SA caused autophagy through the activation of beclin-1, resulting in an impaired renal function and increased creatinine and urea levels. In contrast, the administration of zingerone significantly reduced autophagy in renal tissues [110] (Table 2).