Abstract
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.
Highlights
Chronic kidney disease (CKD) is defined by the gradual reduction in glomerular filtration rate (GFR) and elevation in urinary albumin excretion [1, 2]
The results show that the high-fat diet (HFD)-STZ group displayed a higher level of blood glucose than the normal fat diet (NFD) mice (Fig 1B)
The urine protein-to-creatinine ratio was not elevated in the HFD/STZ group compared to the NFD group. These results indicate that the combination of the HFD and a single low dose of STZ resulted in an UACR increase, which is a prototypical marker of diabetic CKD
Summary
Chronic kidney disease (CKD) is defined by the gradual reduction in glomerular filtration rate (GFR) and elevation in urinary albumin excretion [1, 2]. As causative diseases of CKD, metabolic disorders such as obesity, diabetes mellitus, hyperlipidemia, and hypertension showed strong associations with CKD [1, 7]. Diabetic CKD is the leading cause of ESRD, and CKD prevalence in diabetic patients was known to be up to 40% [8]. In a large cohort study of health men, increased body mass index showed a significantly higher CKD risk after a 14-year follow up [9]. Comorbid illness affected CKD prevalence: patients with comorbidities of metabolic disorders have a greater risk for CKD aggravation than patients with s single disease do [12]. In a cohort of patients with CKD stage 3, multimorbidity of metabolic disorders showed the association with the GFR decrease [13]. HFD-induced nephropathy has been exacerbated by the addition of low dose of streptozotocin (STZ), indicating that the coexistence of metabolic diseases can accelerate CKD [16, 17]
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