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

Abstract

Diabetic kidney disease (DKD) is a widespread chronic microvascular complication of diabetes mellitus (DM), affects almost 30-50% of patients, and represents a leading cause of death of DM. Serotonin or 5-hydroxytryptamine (5-HT) is a multifunctional bioamine that has crucial roles in many physiological pathways. Recently, emerging evidence from experimental and clinical studies has demonstrated that 5-HT is involved in the pathogenesis of diabetic vascular complications. The 5-HT receptor (5-HTR) antagonists exert renoprotective effects by suppressing oxidative stress, suggesting that 5-HTR can be used as a potential target for treating DKD. In this review, therefore, we summarize the published information available for the involvement of 5-HT and 5-HTR antagonists in the pathogenesis of various diabetic complications with a particular focus of DKD. We conclude that 5-HTR is a potential therapeutic target for treating DKD, as it has been successfully applied in animal models and has currently being investigated in randomized and controlled clinical trials.

Figure 1

A model of 5-HT biosynthesis and metabolism in peripheral tissues. 5-HT synthesis is dependent on the enzyme tryptophan hydroxylase (TPH); the released 5-HT is controlled by the autonomous nervous system and released locally into the circulatory system, and most of them are stored in platelets. Reuptake of 5-HT is mediated by SERT. The effects of 5-HT are mediated through 14 serotonergic receptors that have been grouped into seven broad families. All 5-HTRs are G protein-coupled receptors (GPCRs), except 5-HT₃ that is a ligand-gated cationic channel. 5-HT GPCRs were 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.

Figure 2

Mechanism of 5-HT in the mouse pancreatic beta-cells during pregnancy. 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 GSIS. 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.

Figure 3

Model showing the modulation of 5-HT2cR in DM. 5-HT2CR-deficient mice showed that 5-HT may affect glucose and lipid metabolism. Insulin secretion is affected by 5-HT2CR, which is indicative of the possibility that an aberrant 5-HT system could also affect the regulation of energy metabolism. Increased expression of 5-HT2CR in both the hypothalamus and β-cells could mediate a protective strategy to prevent excess energy intake. 5-HT2CR-expressing pro-opiomelanocortin neurons are required to control energy and glucose homeostasis.

Figure 4

Illustration to show the mechanism of 5-HT1D and 5-HT2AR in human T2DM. 5-HT1DR and 5-HT1AR messenger RNA expression was increased in human T2DM islets. The 5-HT2AR antagonist (sarpogrelate hydrochloride) markedly decreased the glycated hemoglobin A1c level. The expression of 5-HT1DR had a negative correlation with somatostatin (SST) and SST receptors (SSTR), whereas the expression of 5-HT2AR did not have any correlation with either SST or any of the SSTRs; this suggests that increased expression of HT1DR in human islet cells, as observed in T2DM islet cells, leads to decreased expression of SST and its receptors.

Figure 5

Mechanisms of 5-HT_2A receptor antagonist contributing to DM-induced cardiovascular complications. Sarpogrelate, a 5-HT2AR antagonist, has been shown to attenuate diabetes-induced cardiovascular complications, which decrease the blood glucose level, inhibit the release of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and reduce 5-HT-induced contraction in aortas through the PI3K and Rho kinase pathway.

Figure 6

Illustration to show the mechanism of 5-HT_2AR in mesangial cells. 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 TGF-β. Stimulation of 5-HT2ARs by 5-HT induces the expression of TGF-β through extracellular signal-regulated kinases.