Beneficial Effects of Sarpogrelate and Rosuvastatin in High Fat Diet/Streptozotocin-Induced Nephropathy in Mice.
Chronic kidney disease (CKD) is a major complication of metabolic disorders such as diabetes mellitus, obesity, and hypertension. Comorbidity of these diseases is the factor exacerbating CKD progression. Statins are commonly used in patients with metabolic disorders to decrease the risk of cardiovascular complications. Sarpogrelate, a selective antagonist of 5-hydroxytryptamine (5-HT) 2A receptor, inhibits platelet aggregation and is used to improve peripheral circulation in diabetic patients. Here, we investigated the effects of sarpogrelate and rosuvastatin on CKD in mice that were subjected to a high fat diet (HFD) for 22 weeks and a single low dose of streptozotocin (STZ, 40 mg/kg). When mice were administrated sarpogrelate (50 mg/kg, p.o.) for 13 weeks, albuminuria and urinary cystatin C excretion were normalized and histopathological changes such as glomerular mesangial expansion, tubular damage, and accumulations in lipid droplets and collagen were significantly improved. Sarpogrelate treatment repressed the HFD/STZ-induced CD31 and vascular endothelial growth factor receptor-2 expressions, indicating the attenuation of glomerular endothelial proliferation. Additionally, sarpogrelate inhibited interstitial fibrosis by suppressing the increases in transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 (PAI-1). All of these functional and histological improvements were also seen in rosuvastatin (20 mg/kg) group and, notably, the combinatorial treatment with sarpogrelate and rosuvastatin showed additive beneficial effects on histopathological changes by HFD/STZ. Moreover, sarpogrelate reduced circulating levels of PAI-1 that were elevated in the HFD/STZ group. As supportive in vitro evidence, sarpogrelate incubation blocked TGF-β1/5-HT-inducible PAI-1 expression in murine glomerular mesangial cells. Taken together, sarpogrelate and rosuvastatin may be advantageous to control the progression of CKD in patients with comorbid metabolic disorders, and particularly, the use of sarpogrelate as adjunctive therapy with statins may provide additional benefits on CKD.
College of pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
Dong-Hyun
DH
Kim
College of pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
Bo-Hyun
BH
Choi
College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeonsangbuk-do, 712-715, Republic of Korea.
Sae-Kwang
SK
Ku
College of pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
Jeong-Hyeon
JH
Park
College of pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
Euichaul
E
Oh
College of pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
Mi-Kyoung
MK
Kwak
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000068718:Rosuvastatin Calcium / Q000494:pharmacology* / Q000627:therapeutic use; D013311:Streptozocin / Q000009:adverse effects*; D013386:Succinates / Q000494:pharmacology* / Q000627:therapeutic use
D017395:Plasminogen Activator Inhibitor 1; D013386:Succinates; C064294:sarpogrelate; D013311:Streptozocin; D000068718:Rosuvastatin Calcium