Serotonin and Its Receptor as a New Antioxidant Therapeutic Target for Diabetic Kidney Disease

1. Introduction

Diabetic kidney disease (DKD) is one of the most epidemic chronic microvascular complications of diabetes mellitus (DM), and it is prevalent in approximately 30–50% of patients with diabetes [1–5]. DKD is the leading cause of chronic and end-stage renal diseases worldwide, and in the past few decades, it has been associated with high morbidity and mortality [6–11].

The pathogenesis of DKD remains not completely understood; however, there is strong experimental evidence that prolonged hyperglycemia leads to the mitochondrial production of reactive oxygen species (ROS), resulting in oxidative stress, which plays a key role in DKD [12–16]. Inflammation induced and exacerbated by oxidative stress is closely associated with the development and progression of DKD.

5-Hydroxytryptamine (5-HT) is a potent vasoactive amine that plays pivotal roles in insulin secretion [17–19], energy metabolism [20], mitochondrial biogenesis [21], the immune system [22, 23], and vascular inflammation [24–27]. However, the functions of 5-HT have not been elucidated yet. Recently, several studies have shown that 5-HT and 5-HT receptors (5-HTR) are involved in the pathogenesis of diabetic vascular complications [17, 28–31]. 5-HTR antagonists have a renoprotective effect by suppressing oxidative stress and inflammatory cytokines [32–35], suggesting that 5-HTR antagonists could be used to treat DKD. This review assesses and describes the current understanding of 5-HT’s involvement in the pathogenesis of DKD and the potential use of 5-HTR antagonists in the clinical treatment of DKD.

2. 5-HT Synthesis and Metabolism and 5-HT Receptors

5-HT is a monoamine neurotransmitter and hormone mainly produced by enterochromaffin cells of the gastrointestinal tract [21]. 5-HT is derived from tryptophan and predominantly stored in circulating platelets, and it is distributed throughout the body to regulate the hormones of several main physiological parameters, such as cardiovascular function [36], insulin secretion [17], energy homeostasis [20], and appetite [37].

5-HT synthesis is dependent on the enzyme tryptophan hydroxylase (TPH), which is encoded by two different genes: tryptophan hydroxylase 1 (Tph1) and Tph2, which are expressed in the peripheral tissues and brain, respectively. Peripheral 5-HT is presumed to be unable to cross the blood-brain barrier. The majority of the peripheral 5-HT is stored in platelets and also present in other tissues and many cells. The released 5-HT is controlled by the autonomous nervous system and released locally into the circulatory system, where it is used for the aggregation of platelets through various stimuli, including atherosclerosis [26, 38]. 5-HT is primarily inactivated by the reuptake of serotonergic neurons that secrete it; this reuptake is mediated by the highly selective plasmalemma 5-HT transporter (5-HTT), which is also known as the serotonin transporter (SERT) [39] (Figure 1).

5-HT produces a myriad of physiological and pathological effects in humans, which are mediated through 14 serotonergic (5-HTergic) receptors that have been grouped into seven broad families (5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆, and 5-HT₇). All 5-HTRs are G protein-coupled receptors (GPCRs), except 5-HT₃ that is a ligand-gated cationic channel. 5-HT GPCR was coupled to all three canonical signaling pathways through G_αi/_O, G_αq/11, and G_s that are involved in the cAMP pathway and allow this receptor family to modulate several biochemical signaling pathways [40].

3. 5-HT in Diabetes and Diabetic Complications

Pancreatic β-cells synthesize and store 5-HT, which is coreleased with insulin [41]. An increased plasma level of 5-HT is a biomarker for diabetic complications, and positive correlations have been established between the plasma 5-hydroxyindoleacetic acid (5-HIAA; the main 5-HT metabolite) level and coronary heart disease [36, 42–45]. Selective serotonergic functional alterations have shown therapeutic relevance in diabetic rats [29, 30, 46]. These studies and their findings have been summarized in the subsequent sections and suggest that 5-HT plays a role in DM.

3.1. 5-HT and Gestational Diabetes

In pregnant mice, prolactin (PRL) stimulates islet prolactin receptors (PRLRs) to trigger a strong upregulation of both isoforms of TPH. TPH upregulation activates 5-HT synthesis in some pancreatic β-cells, which in turn induce glucose-stimulated insulin secretion (GSIS) [47, 48]. The insulin secretion is upregulated by the 5-HT_2B receptor (5-HT_2BR) and downregulated by the 5-HT_1D receptor (5-HT_1DR) in β-cells, making 5-HT a paracrine regulator of β-cell proliferation. 5-HT_3AR channels in wild-type animals allow a 5-HT-mediated influx of cations, depolarizing the resting membrane potential and lowering the threshold for glucose-induced insulin exocytosis [19, 49], as illustrated in Figure 2. Disrupting this balance can result in gestational diabetes.

3.2. 5-HTR and Type 2 DM

Type 2 DM (T2DM) describes a group of metabolic disorders characterized by defects in insulin secretion and insulin sensitivity. Impaired insulin secretion from pancreatic β-cells is an important factor in the etiology of T2DM. However, the complex regulation and mechanism of insulin secretion from β-cells have not been completely elucidated.

High plasma levels of 5-HT have been reported in patients with T2DM, although its potential effect on insulin secretion is unclear. The release of 5-HT from activated platelets is enhanced, decreasing intraplatelet 5-HT content and resulting in increased plasma levels of 5-HT in patients with diabetes [44].

3.2.1. 5-HT_2CR

5-HT_2CR-deficient mice are overweight, exhibit an abnormal feeding behavior, show insulin resistance, and have significantly higher blood glucose concentrations, suggesting that 5-HT may affect glucose and lipid metabolism [17, 20, 50]. Insulin secretion is affected by 5-HT_2CR, which is indicative of the possibility that an aberrant 5-HT system could also affect the regulation of energy metabolism. Increased expression of 5-HT_2CR in both the hypothalamus and β-cells could mediate a protective strategy to prevent excess energy intake. As illustrated in Figure 3, 5-HT_2CR-expressing pro-opiomelanocortin neurons are required to control energy and glucose homeostasis [51].

Although, in human T2DM islet cells, the expression of 5-HT_2CR has not been observed [31], the 5-HT_2CR agonist Belviq (lorcaserin) is the first FDA-approved drug to treat obesity in 15 years [52], and central serotonin 2C receptors regulated glucose homeostasis and may represent a rational target for type 2 diabetes (T2DM) treatment [53, 54]. The 5-HT_2CR agonist m-chlorophenylpiperazine (mCPP) improves glucose homeostasis and insulin sensitivity, and antagonists or genetic loss of 5-HT_2CR impairs glucose homeostasis [55, 56].

3.2.2. 5-HT_1DR and 5-HT_1AR

Bennet et al. [31] reported that 5-HT_1DR and 5-HT_1AR messenger RNA expression was increased in human T2DM islets. 5-HT inhibits both basal- and glucose-induced insulin secretions, and the selective 5-HT_1DR agonist (PNU142633) inhibits GSIS in nondiabetic human islets, whereas the 5-HT_1DR antagonist (LY310762) stimulates GSIS. Interestingly, upon stimulation with 5-HT in isolated islets from patients with T2DM, the inhibitory effect of 5-HT was completely lost (both in basal and stimulatory conditions of glucose); instead, the stimulation of insulin secretion was observed. This indicated that 5-HT acts through increased signaling through the 5-HT_2AR in diabetic conditions. The 5-HT_2AR antagonist (sarpogrelate hydrochloride) markedly decreased the glycated hemoglobin A1c level. The expression of 5-HT_1DR had a negative correlation with somatostatin (SST) and SST receptors (SSTR) 1–5, whereas the expression of 5-HT_2AR did not have any correlation with either SST or any of the SSTRs; this suggests that increased expression of HT_1DR in human islet cells, as observed in T2DM islet cells, leads to decreased expression of SST and its receptors (Figure 4).

3.4. 5-HT_2AR and DM-Induced Vascular Complications

5-HT is a potent vasoactive amine in the cardiovascular system. Cardiovascular disorders of diabetes can be characterized by atherosclerosis [63]. There is strong evidence that impaired vascular endothelial and smooth muscle functions play important roles in the process of DM-induced cardiovascular complications [63, 64]. 5-HT, induced by impaired vascular endothelial cells, is involved in the pathological process of platelet aggregation [45], thrombogenesis [65], contraction of carotid arteries [66], and arteriogenesis [67] in DM-induced vascular complications through 5-HT_2AR.

Sarpogrelate, a 5-HT2AR antagonist, has been shown to attenuate diabetes-induced cardiovascular complications, which decrease the blood glucose level [66], inhibit the release of intercellular adhesion molecule-1(ICAM-1) and vascular cell adhesion molecule-1(VCAM-1) [68], and reduce 5-HT-induced contraction in aortas through the PI3K [66] and Rho kinase [69] pathway, as illustrated in Figure 5.

4. Mechanism of the 5-HTR Antagonist for Treating DKD

DKD is a main microvascular complication of diabetes and the most common cause of end-stage renal disease strongly associated with cardiovascular morbidity and mortality, which cause an enormous burden on affected patients and health care systems [70]. Histopathological changes associated with DKD are characterized by thickening of the glomerular basement membrane; podocyte effacement and hypertrophy; accumulation of extracellular matrix and proteins, such as collagen and fibronectin; and the hyalinization of afferent and efferent glomerular arterioles [71, 72].

Studies have indicated that inflammation is an important mechanism in the pathogenesis of DKD that triggers a complex network of pathophysiological events that modulate intracellular signaling pathways involving protein kinase C [73–75] and ROS [76–78] and act in a concerted manner to induce transcription factors, cytokines, chemokines, and growth factors during hyperglycemia [13–15, 79–81]. Although many factors have been implicated in the pathogenesis of DKD, inflammation is believed to play a fundamental role in the early development and progression of DKD [14, 71, 78, 80, 82]. Drugs with anti-inflammatory effects have been used as a new clinical approach for treating DKD.

Previous reports have indicated that the increased plasma concentrations of 5-HT or its metabolite (5-HIAA) are valuable biomarkers for estimating the DKD-associated risk during the early stages of the disease [35, 83, 84]. 5-HT has been shown to enhance the production of type IV collagen by human mesangial cells, and its production is mediated by the activation of protein kinase C and a subsequent increase in active transforming growth factor-β (TGF-β) [85]. Stimulation of 5-HT_2ARs by 5-HT induces the expression of TGF-β through extracellular signal-regulated kinases, a key mediator of proliferative and fibrotic signals in mesangial cells [86–89], as illustrated in Figure 6.

Studies have shown that 5-HTR antagonists are effective in preventing diabetic nephropathy. Sarpogrelate, a 5-HT2 subtype 2A antagonist [33, 34], reduced albuminuria in the early stages of DKD by improving glomerular endothelial function through the reduction in glomerular platelet activation and an increase in serum adiponectin concentrations in a diabetic animal model. Ogawa et al. [90] and Park et al. [91] found that sarpogrelate can reduce albuminuria and plasma and urinary monocyte chemoattractant protein-1 levels in patients with DKD. Tropisetron, a 5-HT₃ receptor antagonist, can attenuate early DM through calcineurin inhibition and by suppressing oxidative stress and some inflammatory cytokines in streptozotocin-induced diabetic rats [32].

5. Conclusions

There is an increasing repertoire of evidence supporting 5-HT as a causative agent for increased ROS generation in DM. Since 5-HT mediates accelerated atherosclerosis in diabetes, pharmacological inhibition of the 5-HT receptor presents an attractive therapeutic strategy for patients with diabetes to attenuate the development of nephropathy and macrovascular complications. A better understanding of the role of these new receptor targets in the context of DKD will facilitate the development of novel therapeutic strategies that can be successfully translated into clinical applications.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.