Sarpogrelate hydrochloride ameliorates diabetic nephropathy associated with inhibition of macrophage activity and inflammatory reaction in db/db mice
June
Sarpogrelate hydrochloride ameliorates diabetic nephropathy associated with inhibition of macrophage activity and inflammatory reaction in db/db mice
Eun Soo Lee 1 2
Mi Young Lee 1 2
Mi-Hye Kwon 1 2
Hong Min Kim 1 2
Jeong Suk Kang 0 2
You Mi Kim 1 2
Eun Young Lee 0 2
Choon Hee Chung 1 2
0 Department of Internal Medicine, Soonchunhyang University Cheonan Hospital , Cheonan , Korea
1 Department of Internal Medicine, Yonsei University Wonju College of Medicine , Wonju , Korea
2 Editor: Rajesh Mohanraj, Faculty of Medicine & Health Science , UNITED ARAB EMIRATES
The aim of this study was to evaluate the effects of sarpogrelate hydrochloride (SH), a selective serotonin 2A receptor antagonist, on diabetic nephropathy in a type 2 diabetes mouse model. We treated db/m and db/db mice with SH (30 mg/kg/day) for 12 weeks. Rat renal proximal tubule cells (NRK-52E) and mouse macrophages (Raw 264.7) were stimulated by high glucose (30 mM glucose) or LPS (100 ng/ml) with or without SH (20 μM). We found that SH treatment increased serum adiponectin level and decreased urinary albumin, macrophage infiltration to glomeruli, and renal inflammatory and fibrosis signals, which were highly expressed in diabetic mice. Proximal tubule cells treated with high glucose (30 mM) also showed increased inflammatory and fibrosis signals. However, SH (20 μM) treatment reduced these changes. Moreover, SH treatment inhibited LPS-stimulated macrophage migration and activation. These findings suggest that SH ameliorates diabetic nephropathy not only by suppressing macrophage infiltration, but also by anti-inflammatory and antifibrotic effects.
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Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Funding: This research was supported by Basic
Science Research Program through the National
Research Foundation of Korea (NRF) funded by the
Ministry of Education (2015R1D1A1A02060785,
2015R1A6A1A03032522) to EYL, and the research
grant from Yonsei University Wonju College of
Medicine (YUWCM-2009-23) to MYL. The funders
Introduction
Diabetic nephropathy (DN) is a progressive kidney disease that increases the morbidity and
mortality of patients with diabetes globally. Several studies have shown that inflammatory cell
accumulation in the kidney triggers renal inflammation, which is a key factor in the
development and progression of DN [
1,2
]. Macrophages, one type of inflammatory cell, are known to
mediate renal inflammation and fibrosis [3]. In the kidney, renal proximal tubular cells play an
important role in the pathogenesis of DN. Inflammatory cells release mediators such as
complements, antibodies, cytokines and chemokines, which activate proximal tubular cells and
leading to the overproduction of matrix components causing renal fibrosis [
4
].
had no role in study design, data collection and
analysis, decision to publish, or preparation of the
manuscript.
Serotonin (5-hydroxytryptamine, 5HT), a neurotransmitter released by activated platelets,
acts on the brain and gastrointestinal tract. It has various functions and plays a role in
regulating mood, urine storage, sleep, body temperature, food intake, and intestinal motility [
5
]. In
addition, serotonin has powerful effects on vasoconstriction [
6
]. In diabetic patients, plasma
serotonin level was elevated and associated with the development of cardiovascular
complications [
7
]. Takahashi et al. showed that serotonin induced renal vasoconstriction in dog kidneys
[
8
]. Moreover, serotonin increased mesangial cell proliferation, extracellular matrix synthesis,
and fibrosis in diabetic nephropathy [9±11].
The action of serotonin is mediated by serotonin receptors, which are classified into seven
subfamilies, from 5-HT1 to 5-HT7. One of these serotonin receptors, 5HT-2A, is found in
mesangial cells, and serotonin modulates cytokine and chemokine production in
lipopolysaccharide (LPS)-primed monocytes via serotonin receptors [12±14].
Sarpogrelate hydrochloride (SH), a selective 5HT-2A antagonist, is used clinically for the
treatment of vascular inflammation and atherosclerosis [
15
]. A few studies have shown that
SH mitigates albuminuria in diabetic nephropathy by hindering glomerular platelet activation
[
16,17
]. However, the exact mechanisms underlying the role of SH in diabetic nephropathy are
not fully understood. Thus, we investigated the effects and mechanisms of SH in diabetic
nephropathy.
Materials and methods
Animal experiments
Male db/m and db/db mice in a C57BLKs/J background (6 weeks old) were purchased from
Daehan Biolink (Chungbuk, Korea) and randomly divided into four groups (n = 7 in each
group) as follows: 1) normal control (NC), 2) normal control treated with SH (NC+SH), 3)
diabetic group (DB), and 4) diabetic group treated with SH (DB+SH). The SH (30 mg/kg/day)
was administered via oral gavage for 12 weeks. Animals were housed at a constant temperature
(20 ± 2ÊC) and humidity level (50±60%) (...truncated)