Journal of Diabetes Research
Volume 2017 (2017), Article ID 7680576, 9 pages
https://doi.org/10.1155/2017/7680576

Review Article

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

Yu Yang,¹ Hui Huang,1,2 Zheng Xu,2,3 and Jun-kai Duan⁴

¹Department of Endocrinology, Metabolism, and Genetics, Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi, China
²Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA
³Department of Cardiovascular Disorders, The First Hospital of Jilin University, Changchun, China
⁴Department of Cardiovascular Disorders, Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi, China

Correspondence should be addressed to Yu Yang; yyhhjxey@gmail.com

Received 2 May 2017; Accepted 13 July 2017; Published 8 August 2017

Academic Editor: Robertina Giacconi

Copyright © 2017 Yu Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

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).

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 Gαi/O, Gαq/11, and Gs that are involved in the cAMP pathway and allow this receptor family to modulate several biochemical signaling pathways.

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 Gαi/O, Gαq/11, and Gs 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-HT2B receptor (5-HT2BR) and downregulated by the 5-HT1D receptor (5-HT1DR) in β-cells, making 5-HT a paracrine regulator of β-cell proliferation. 5-HT3AR 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.

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-HT2B receptor (5-HT2BR) and downregulated by the 5-HT1D receptor (5-HT1DR) in β-cells, making 5-HT a paracrine regulator of β-cell proliferation. 5-HT3AR 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.

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-HT2CR

5-HT2CR-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-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. As illustrated in Figure 3, 5-HT2CR-expressing pro-opiomelanocortin neurons are required to control energy and glucose homeostasis [51].

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.

Although, in human T2DM islet cells, the expression of 5-HT2CR has not been observed [31], the 5-HT2CR 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-HT2CR agonist m-chlorophenylpiperazine (mCPP) improves glucose homeostasis and insulin sensitivity, and antagonists or genetic loss of 5-HT2CR impairs glucose homeostasis [55, 56].

3.2.2. 5-HT1DR and 5-HT1AR

Bennet et al. [31] reported that 5-HT1DR and 5-HT1AR messenger RNA expression was increased in human T2DM islets. 5-HT inhibits both basal- and glucose-induced insulin secretions, and the selective 5-HT1DR agonist (PNU142633) inhibits GSIS in nondiabetic human islets, whereas the 5-HT1DR 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-HT2AR in diabetic conditions. 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) 1–5, 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 4).

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.

3.3. 5-HT as an Immunomodulator in DM

Although several physiological causes that lead to DM remain unknown, evidence suggests that autoimmunity plays an important role in DM and diabetic complications. There is an increasingly collective perspective regarding the association of 5-HT with the activation of immunoinflammatory pathways and the onset of autoimmune reactions. Almost all the circulating 5-HT are found in platelets and released following platelet activation, on contact with damaged endothelium or induced by ischemia, indicating that 5-HT also contributes to the innate and adaptive immune responses [22, 57]. 5-HT stimulation increases murine peritoneal macrophage production of proinflammatory cytokines [25]. The expression of 5-HTRs has been identified in rodent and human innate immune cells, which include neutrophils, eosinophils, monocytes, macrophages, dendritic cells, mast cells, and natural killer cells [58].

5-HT was identified as an immunomodulator owing to its ability to stimulate or inhibit inflammation. Moreover, 5-HT has immunomodulatory effects that are induced by activating 5-HTR and SERT, which are differentially expressed in many leukocytes. Arthritis [59], systemic sclerosis [38, 60], lung fibrosis [61], and allergic asthma [62] are all associated with changes in the serotonergic system, which is associated with leukocytes.

3.4. 5-HT2AR 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-HT2AR.

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.

Figure 5: Mechanisms of 5-HT2A 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.

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-HT2ARs 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.

Figure 6: Illustration to show the mechanism of 5-HT2AR 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.

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.

Abbreviations

5-HT: | 5-Hydroxytryptamine
TPH: | Tryptophan hydroxylase
AADC: | Unbiquitous aromatic L-amino acid decarboxylase
5-HTT: | 5-HT transporter
Cys-loop LGICs: | Cys-loop ligand-gated ion channels
5-HTT (SERT): | 5-Hydroxytryptamine transporter
GPCRs: | G protein-coupled receptors
AC: | Adenylyl cyclase
cAMP: | Cyclic adenosine monophosphate
PIP2: | Phosphatidylinositol 4,5-bisphosphate
IP3: | Inositol trisphosphate
DAG: | Diacylglycerol
PRL: | Prolactin
PRLR: | Islet prolactin receptors
GSIS: | Glucose-stimulated insulin secretion
SST: | Somatostatin
SSTR: | SST receptors
Rho: | Ras homolog gene family member
ICAM-1: | Intercellular adhesion molecule-1
VCAM-1: | Vascular cell adhesion molecule-1
TGF-β: | Transforming growth factor-β
PKC: | Protein kinase C
ROS: | Reactive oxygen species
NADP: | Nicotinamide adenine dinucleotide phosphate
ERK: | Extracellular signal-regulated kinases.

Conflicts of Interest

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

Acknowledgments

This work was supported in part by the National Key Research and Development Program of China (2016YFC1305301) and the National Natural Science Foundation of China (no. 81460501).

References

I. H. de Boer, T. C. Rue, Y. N. Hall, P. J. Heagerty, N. S. Weiss, and J. Himmelfarb, “Temporal trends in the prevalence of diabetic kidney disease in the United States,” The Journal of the American Medical Association, vol. 305, pp. 2532–2539, 2011.

S. P. Silveiro, G. N. Araujo, M. N. Ferreira, F. D. Souza, H. M. Yamaguchi, and E. G. Camargo, “Chronic kidney disease epidemiology collaboration (ckd-epi) equation pronouncedly underestimates glomerular filtration rate in type 2 diabetes,” Diabetes Care, vol. 34, pp. 2353–2355, 2011.

A. S. Krolewski, “Progressive renal decline: the new paradigm of diabetic nephropathy in type 1 diabetes,” Diabetes Care, vol. 38, pp. 954–962, 2015.

R. Amin, B. Widmer, A. T. Prevost et al., “Risk of microalbuminuria and progression to macroalbuminuria in a cohort with childhood onset type 1 diabetes: prospective observational study,” British Medical Journal, vol. 336, pp. 697–701, 2008.

A. Kowalski, A. Krikorian, and E. V. Lerma, “Diabetes and chronic kidney disease,” Disease-a-Month, vol. 61, pp. 378–386, 2015.

J. J. Liu, S. C. Lim, L. Y. Yeoh et al., “Ethnic disparities in risk of cardiovascular disease, end-stage renal disease and all-cause mortality: a prospective study among Asian people with type 2 diabetes,” Diabetic Medicine, vol. 33, pp. 332–339, 2016.

C. C. Lim, B. W. Teo, P. G. Ong et al., “Chronic kidney disease, cardiovascular disease and mortality: a prospective cohort study in a multi-ethnic Asian population,” European Journal of Preventive Cardiology, vol. 22, pp. 1018–1026, 2015.

K. R. Tuttle, G. L. Bakris, R. W. Bilous et al., “Diabetic kidney disease: a report from an ADA Consensus Conference,” Diabetes Care, vol. 37, pp. 2864–2883, 2014.

E. T. Rosolowsky, J. Skupien, A. M. Smiles et al., “Risk for ESRD in type 1 diabetes remains high despite renoprotection,” Journals of the American Society of Nephrology, vol. 22, pp. 545–553, 2011.

R. Saran, Y. Li, B. Robinson et al., “US renal data system 2015 annual data report: epidemiology of kidney disease in the United States,” American Journal of Kidney Diseases, vol. 67, pp. A7–A8, 2016.

S. B. Ghaderian, F. Hayati, S. Shayanpour, and S. S. Beladi Mousavi, “Diabetes and end-stage renal disease; a review article on new concepts,” Journal of Renal Injury Prevention, vol. 4, pp. 28–33, 2015.

H. B. Lee, “Reactive oxygen species-regulated signaling pathways in diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 14, pp. 241S–245S, 2003.

K. Susztak, A. C. Raff, M. Schiffer, and E. P. Bottinger, “Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy,” Diabetes, vol. 55, pp. 225–233, 2006.

L. E. Fridlyand and L. H. Philipson, “Oxidative reactive species in cell injury: mechanisms in diabetes mellitus and therapeutic approaches,” Annals of the New York Academy of Sciences, vol. 1066, pp. 136–151, 2005.

G. Al-Kafaji, M. A. Sabry, and C. Skrypnyk, “Time-course effect of high-glucose-induced reactive oxygen species on mitochondrial biogenesis and function in human renal mesangial cells,” Cell Biology International, vol. 40, pp. 36–48, 2016.

L. Sun, R. K. Dutta, P. Xie, and Y. S. Kanwar, “Myo-inositol oxygenase overexpression accentuates generation of reactive oxygen species and exacerbates cellular injury following high glucose ambience: a new mechanism relevant to the pathogenesis of diabetic nephropathy,” The Journal of Biological Chemistry, vol. 291, pp. 5688–5707, 2016.

K. Kim, C. M. Oh, M. Ohara-Imaizumi et al., “Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state,” Endocrinology, vol. 156, pp. 444–452, 2015.

Q. Zhang, Y. Zhu, W. Zhou, L. Gao, L. Yuan, and X. Han, “Serotonin receptor 2c and insulin secretion,” PLoS One, vol. 8, article e54250, 2013.

Y. Ohta, Y. Kosaka, N. Kishimoto et al., “Convergence of the insulin and serotonin programs in the pancreatic beta-cell,” Diabetes, vol. 60, pp. 3208–3216, 2011.

C. M. Oh, J. Namkung, Y. Go et al., “Regulation of systemic energy homeostasis by serotonin in adipose tissues,” Nature Communications, vol. 6, p. 6794, 2015.

K. A. Rasbach, J. A. Funk, T. Jayavelu, P. T. Green, and R. G. Schnellmann, “5-Hydroxytryptamine receptor stimulation of mitochondrial biogenesis,” The Journal of Pharmacology and Experimental Therapeutics, vol. 332, pp. 632–639, 2010.

R. Arreola, E. Becerril-Villanueva, C. Cruz-Fuentes et al., “Immunomodulatory effects mediated by serotonin,” Journal of Immunology Research, vol. 2015, Article ID 354957, 21 pages, 2015.

G. P. Ahern, “5-HT and the immune system,” Current Opinion in Pharmacology, vol. 11, pp. 29–33, 2011.

G. A. Ramirez, S. Franchini, P. Rovere-Querini, M. G. Sabbadini, A. A. Manfredi, and N. Maugeri, “The role of platelets in the pathogenesis of systemic sclerosis,” Frontiers in Immunology, vol. 3, p. 160, 2012.

M. de Las Casas-Engel and A. L. Corbi, “Serotonin modulation of macrophage polarization: inflammation and beyond,” Advances in Experimental Medicine and Biology, vol. 824, pp. 89–115, 2014.

M. Idzko, S. Pitchford, and C. Page, “Role of platelets in allergic airway inflammation,” The Journal of Allergy and Clinical Immunology, vol. 135, pp. 1416–1423, 2015.

J. J. Worthington, “The intestinal immunoendocrine axis: novel cross-talk between enteroendocrine cells and the immune system during infection and inflammatory disease,” Biochemical Society Transactions, vol. 43, pp. 727–733, 2015.

T. Sugiura, Y. Dohi, S. Yamashita, Y. Hirowatari, S. Fujii, and N. Ohte, “Serotonin in peripheral blood reflects oxidative stress and plays a crucial role in atherosclerosis: novel insights toward holistic anti-atherothrombotic strategy,” Atherosclerosis, vol. 246, pp. 157–160, 2016.

K. Nonogaki and T. Kaji, “Mosapride, a selective serotonin 5-HT4 receptor agonist, and alogliptin, a selective dipeptidyl peptidase-4 inhibitor, exert synergic effects on plasma active glp-1 levels and glucose tolerance in mice,” Diabetes Research and Clinical Practice, vol. 110, pp. e18–e21, 2015.

F. Montastruc, A. Palmaro, H. Bagheri, L. Schmitt, J. L. Montastruc, and M. Lapeyre-Mestre, “Role of serotonin 5-HT2c and histamine h1 receptors in antipsychotic-induced diabetes: a pharmacoepidemiological-pharmacodynamic study in vigibase,” European Neuropsychopharmacology, vol. 25, pp. 1556–1565, 2015.

H. Bennet, A. Balhuizen, A. Medina et al., “Altered serotonin (5-HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes,” Peptides, vol. 71, pp. 113–120, 2015.

A. Barzegar-Fallah, H. Alimoradi, F. Asadi, A. R. Dehpour, M. Asgari, and M. Shafiei, “Tropisetron ameliorates early diabetic nephropathy in streptozotocin-induced diabetic rats,” Clinical and Experimental Pharmacology & Physiology, vol. 42, pp. 361–368, 2015.

S. Kobayashi, M. Satoh, T. Namikoshi et al., “Blockade of serotonin 2A receptor improves glomerular endothelial function in rats with streptozotocin-induced diabetic nephropathy,” Clinical and Experimental Nephrology, vol. 12, pp. 119–125, 2008.

T. Takahashi, M. Yano, J. Minami et al., “Sarpogrelate hydrochloride, a serotonin2A receptor antagonist, reduces albuminuria in diabetic patients with early-stage diabetic nephropathy,” Diabetes Research and Clinical Practice, vol. 58, pp. 123–129, 2002.

K. Hara, Y. Hirowatari, Y. Shimura, and H. Takahashi, “Serotonin levels in platelet-poor plasma and whole blood in people with type 2 diabetes with chronic kidney disease,” Diabetes Research and Clinical Practice, vol. 94, pp. 167–171, 2011.

S. Watanabe, T. Matsumoto, M. Oda et al., “Insulin augments serotonin-induced contraction via activation of the IR/PI3K/PDK1 pathway in the rat carotid artery,” Pflügers Archiv-European Journal of Physiology, vol. 468, no. 4, pp. 667–677, 2016.

C. M. Oh, S. Park, and H. Kim, “Serotonin as a new therapeutic target for diabetes mellitus and obesity,” Diabetes & Metabolism Journal, vol. 40, pp. 89–98, 2016.

K. Hara, Y. Hirowatari, M. Yoshika, Y. Komiyama, Y. Tsuka, and H. Takahashi, “The ratio of plasma to whole-blood serotonin may be a novel marker of atherosclerotic cardiovascular disease,” The Journal of Laboratory and Clinical Medicine, vol. 144, pp. 31–37, 2004.

B. A. Davis, A. Nagarajan, L. R. Forrest, and S. K. Singh, “Mechanism of paroxetine (paxil) inhibition of the serotonin transporter,” Scientific Reports, vol. 6, article 23789, 2016.

J. D. McCorvy and B. L. Roth, “Structure and function of serotonin G protein-coupled receptors,” Pharmacology & Therapeutics, vol. 150, pp. 129–142, 2015.

G. Jaim-Etcheverry and L. M. Zieher, “Electron microscopic cytochemistry of 5-hydroxytryptamine (5-HT) in the beta cells of guinea pig endocrine pancreas,” Endocrinology, vol. 83, pp. 917–923, 1968.

A. Hameed, M. Ajmal, M. Nasir, and M. Ismail, “Genetic association analysis of serotonin transporter polymorphism (5-HTTLPR) with type 2 diabetes patients of Pakistani population,” Diabetes Research and Clinical Practice, vol. 108, pp. 67–71, 2015.

D. R. Gehlert and J. Shaw, “5-Hydroxytryptamine 1A (5HT1A) receptors mediate increases in plasma glucose independent of corticosterone,” European Journal of Pharmacology, vol. 745, pp. 91–97, 2014.

E. Ezzeldin, W. A. Souror, T. El-Nahhas, A. N. Soudi, and A. A. Shahat, “Biochemical and neurotransmitters changes associated with tramadol in streptozotocin-induced diabetes in rats,” BioMed Research International, vol. 2014, Article ID 238780, 9 pages, 2014.

Y. Hasegawa, A. Suehiro, S. Higasa, M. Namba, and E. Kakishita, “Enhancing effect of advanced glycation end products on serotonin-induced platelet aggregation in patients with diabetes mellitus,” Thrombosis Research, vol. 107, pp. 319–323, 2002.

K. V. Derkach, V. M. Bondareva, O. V. Chistyakova, L. M. Berstein, and A. O. Shpakov, “The effect of long-term intranasal serotonin treatment on metabolic parameters and hormonal signaling in rats with high-fat diet/low-dose streptozotocin-induced type 2 diabetes,” International Journal of Endocrinology, vol. 2015, Article ID 245459, 17 pages, 2015.

L. Goyvaerts, A. Schraenen, and F. Schuit, “Serotonin competence of mouse beta cells during pregnancy,” Diabetologia, vol. 59, no. 7, pp. 1356–1363, 2016.

M. Ohara-Imaizumi, H. Kim, M. Yoshida et al., “Serotonin regulates glucose-stimulated insulin secretion from pancreatic beta cells during pregnancy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, pp. 19420–19425, 2013.

N. Paulmann, M. Grohmann, J. P. Voigt et al., “Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation,” PLoS Biology, vol. 7, article e1000229, 2009.

J. D. Crane, R. Palanivel, E. P. Mottillo et al., “Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis,” Nature Medicine, vol. 21, pp. 166–172, 2015.

E. D. Berglund, C. Liu, J. W. Sohn et al., “Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis,” The Journal of Clinical Investigation, vol. 123, pp. 5061–5070, 2013.

E. Colman, J. Golden, M. Roberts, A. Egan, J. Weaver, and C. Rosebraugh, “The FDA’s assessment of two drugs for chronic weight management,” The New England Journal of Medicine, vol. 367, pp. 1577–1579, 2012.

O. J. Marston, A. S. Garfield, and L. K. Heisler, “Role of central serotonin and melanocortin systems in the control of energy balance,” European Journal of Pharmacology, vol. 660, pp. 70–79, 2011.

D. D. Lam and L. K. Heisler, “Serotonin and energy balance: molecular mechanisms and implications for type 2 diabetes,” Expert Reviews in Molecular Medicine, vol. 9, pp. 1–24, 2007.

J. Qiu, C. Xue, M. A. Bosch et al., “Serotonin 5-hydroxytryptamine2C receptor signaling in hypothalamic proopiomelanocortin neurons: role in energy homeostasis in females,” Molecular Pharmacology, vol. 72, pp. 885–896, 2007.

J. M. Wade, P. Juneja, A. W. MacKay et al., “Synergistic impairment of glucose homeostasis in ob/ob mice lacking functional serotonin 2C receptors,” Endocrinology, vol. 149, pp. 955–961, 2008.

G. Csaba, “Hormones in the immune system and their possible role. A critical review,” Acta Microbiologica et Immunologica Hungarica, vol. 61, pp. 241–260, 2014.

S. Zheng, S. Coventry, L. Cai et al., “Renal protection by genetic deletion of the atypical chemokine receptor ACKR2 in diabetic OVE mice,” Journal of Diabetes Research, vol. 2016, Article ID 5362506, 11 pages, 2016.

Y. Chabbi-Achengli, T. Coman, C. Collet et al., “Serotonin is involved in autoimmune arthritis through th17 immunity and bone resorption,” The American Journal of Pathology, vol. 186, pp. 927–937, 2016.

D. Hirigoyen, P. I. Burgos, V. Mezzano et al., “Inhibition of angiogenesis by platelets in systemic sclerosis patients,” Arthritis Research & Therapy, vol. 17, p. 332, 2015.

P. R. Pereira, M. C. Oliveira-Junior, B. MacKenzie et al., “Exercise reduces lung fibrosis involving serotonin/Akt signaling,” Medicine and Science in Sports and Exercise, vol. 48, no. 7, pp. 1276–1284, 2016.

G. Ahangari, S. E. Koochak, L. M. Amirabad, and G. D. Deilami, “Investigation of 5-HT2A gene expression in PBMCs of patients with allergic asthma,” Inflammation & Allergy Drug Targets, vol. 14, pp. 60–64, 2015.

J. M. Forbes and M. E. Cooper, “Mechanisms of diabetic complications,” Physiological Reviews, vol. 93, pp. 137–188, 2013.

K. E. Porter and K. Riches, “The vascular smooth muscle cell: a therapeutic target in type 2 diabetes?” Clinical Science (London, England: 1979), vol. 125, pp. 167–182, 2013.

K. Yamada, H. Niki, H. Nagai, M. Nishikawa, and H. Nakagawa, “Serotonin potentiates high-glucose-induced endothelial injury: the role of serotonin and 5-HT2A receptors in promoting thrombosis in diabetes,” Journal of Pharmacological Sciences, vol. 119, pp. 243–250, 2012.

T. Matsumoto, S. Watanabe, K. Taguchi, and T. Kobayashi, “Mechanisms underlying increased serotonin-induced contraction in carotid arteries from chronic type 2 diabetic Goto-Kakizaki rats,” Pharmacological Research, vol. 87, pp. 123–132, 2014.

S. C. Bir, M. Fujita, A. Marui et al., “New therapeutic approach for impaired arteriogenesis in diabetic mouse hindlimb ischemia,” Circulation Journal: Official Journal of the Japanese Circulation Society, vol. 72, pp. 633–640, 2008.

Y. Su, N. Mao, M. Li et al., “Sarpogrelate inhibits the expression of ICAM-1 and monocyte-endothelial adhesion induced by high glucose in human endothelial cells,” Molecular and Cellular Biochemistry, vol. 373, pp. 195–199, 2013.

P. M. Nelson, J. S. Harrod, and K. G. Lamping, “5HT(2a) and 5HT(2b) receptors contribute to serotonin-induced vascular dysfunction in diabetes,” Experimental Diabetes Research, vol. 2012, Article ID 398406, 11 pages, 2012.

E. R. Seaquist, “Addressing the burden of diabetes,” The Journal of the American Medical Association, vol. 311, pp. 2267-2268, 2014.

C. Mora-Fernandez, V. Dominguez-Pimentel, M. M. de Fuentes, J. L. Gorriz, A. Martinez-Castelao, and J. F. Navarro-Gonzalez, “Diabetic kidney disease: from physiology to therapeutics,” The Journal of Physiology, vol. 592, pp. 3997–4012, 2014.

G. Wolf, “New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology,” European Journal of Clinical Investigation, vol. 34, pp. 785–796, 2004.

J. Wang, F. Qin, A. Deng, and L. Yao, “Different localization and expression of protein kinase C-beta in kidney cortex of diabetic nephropathy mice and its role in telmisartan treatment,” American Journal of Translational Research, vol. 7, pp. 1116–1125, 2015.

J. Yang and J. Zhang, “Influence of protein kinase C (PKC) on the prognosis of diabetic nephropathy patients,” International Journal of Clinical and Experimental Pathology, vol. 8, pp. 14925–14931, 2015.

K. Zhu, T. Kakehi, M. Matsumoto et al., “NADPH oxidase NOX1 is involved in activation of protein kinase C and premature senescence in early stage diabetic kidney,” Free Radical Biology & Medicine, vol. 83, pp. 21–30, 2015.

J. C. Jha, V. Thallas-Bonke, C. Banal et al., “Podocyte-specific NOX4 deletion affords renoprotection in a mouse model of diabetic nephropathy,” Diabetologia, vol. 59, pp. 379–389, 2016.

Y. Gorin, R. C. Cavaglieri, K. Khazim et al., “Targeting NADPH oxidase with a novel dual NOX1/NOX4 inhibitor attenuates renal pathology in type 1 diabetes,” American Journal of Physiology Renal Physiology, vol. 308, pp. F1276–F1287, 2015.

A. B. Bhatti and M. Usman, “Drug targets for oxidative podocyte injury in diabetic nephropathy,” Cureus, vol. 7, article e393, 2015.

S. C. Tang, W. H. Yiu, M. Lin, and K. N. Lai, “Diabetic nephropathy and proximal tubular damage,” Journal of Renal Nutrition: The Official Journal of the Council on Renal Nutrition of the National Kidney Foundation, vol. 25, pp. 230–233, 2015.

P. M. Garcia-Garcia, M. A. Getino-Melian, V. Dominguez-Pimentel, and J. F. Navarro-Gonzalez, “Inflammation in diabetic kidney disease,” World Journal of Diabetes, vol. 5, pp. 431–443, 2014.

L. Nalysnyk, M. Hernandez-Medina, and G. Krishnarajah, “Glycaemic variability and complications in patients with diabetes mellitus: evidence from a systematic review of the literature,” Diabetes, Obesity & Metabolism, vol. 12, pp. 288–298, 2010.

W. J. Ni, L. Q. Tang, and W. Wei, “Research progress in signalling pathway in diabetic nephropathy,” Diabetes/Metabolism Research and Reviews, vol. 31, pp. 221–233, 2015.

J. Saito, E. Suzuki, Y. Tajima, K. Takami, Y. Horikawa, and J. Takeda, “Increased plasma serotonin metabolite 5-hydroxyindole acetic acid concentrations are associated with impaired systolic and late diastolic forward flows during cardiac cycle and elevated resistive index at popliteal artery and renal insufficiency in type 2 diabetic patients with microalbuminuria,” Endocrine Journal, vol. 63, no. 1, pp. 69–76, 2016.

M. Fukui, E. Shiraishi, M. Tanaka et al., “Plasma serotonin is a predictor for deterioration of urinary albumin excretion in men with type 2 diabetes mellitus,” Metabolism: Clinical and Experimental, vol. 58, pp. 1076–1079, 2009.

M. Kasho, M. Sakai, T. Sasahara et al., “Serotonin enhances the production of type IV collagen by human mesangial cells,” Kidney International, vol. 54, pp. 1083–1092, 1998.

J. S. Grewal, L. M. Luttrell, and J. R. Raymond, “G protein-coupled receptors desensitize and down-regulate epidermal growth factor receptors in renal mesangial cells,” The Journal of Biological Chemistry, vol. 276, pp. 27335–27344, 2001.

J. S. Grewal, Y. V. Mukhin, M. N. Garnovskaya, J. R. Raymond, and E. L. Greene, “Serotonin 5-HT2A receptor induces TGF-beta1 expression in mesangial cells via ERK: proliferative and fibrotic signals,” The American Journal of Physiology, vol. 276, pp. F922–F930, 1999.

N. Pizzinat, J. P. Girolami, A. Parini, C. Pecher, and C. Ordener, “Serotonin metabolism in rat mesangial cells: involvement of a serotonin transporter and monoamine oxidase a,” Kidney International, vol. 56, pp. 1391–1399, 1999.

C. G. Nebigil, M. N. Garnovskaya, R. F. Spurney, and J. R. Raymond, “Identification of a rat glomerular mesangial cell mitogenic 5-HT2A receptor,” The American Journal of Physiology, vol. 268, pp. F122–F127, 1995.

S. Ogawa, T. Mori, K. Nako, T. Ishizuka, and S. Ito, “Reduced albuminuria with sarpogrelate is accompanied by a decrease in monocyte chemoattractant protein-1 levels in type 2 diabetes,” Clinical Journal of the American Society of Nephrology, vol. 3, pp. 362–368, 2008.

S. Y. Park, S. Y. Rhee, S. Oh et al., “Evaluation of the effectiveness of sarpogrelate on the surrogate markers for macrovascular complications in patients with type 2 diabetes,” Endocrine Journal, vol. 59, pp. 709–716, 2012.