Combinational Use of Antiplatelet Medication Sarpogrelate with Therapeutic Drug Rosuvastatin in Treating High-Cholesterol Diet-Induced Chronic Kidney Disease in ApoE-Deficient Mice.

Jingyi Xu,Zuowei Pei,Xinyan Chen,Lu Wang,Yichen Lin,Xiaodan Liu,Meng Yu,Xiang Li

doi:10.1155/2020/1809326

Abstract

A number of metabolic disorders, including hyperlipidemia, potentially cause chronic kidney disease (CKD), one of their major chronic complications and comorbidities. Rosuvastatin is one of the widely used antiatherogenic drugs among hyperlipidemic patients. Meanwhile, sarpogrelate is not only a 5-hydroxytryptamine receptor antagonist but also an antiplatelet agent, inhibiting platelet-stimulated blood coagulation and improving peripheral circulation. In this study, a combination of sarpogrelate and/or rosuvastatin was used on CKD mice induced by a high-fat diet for 8 weeks. The mice were tested for pathological changes using histological evaluation. Tremendous alterations were found, including a remarked increase in total cholesterol and low-density lipoprotein cholesterol levels, glomerular endothelial proliferation, and mesangial expansion. Also, tubular damage and extracellular matrix accumulation occurred, namely, a marked increase in the macula densa, scattered and apoptotic loss of the apical brush border with vacuolated basophilic cytoplasm and heavily stained nuclei, and expanded Bowman's space, which were at least partially ameliorated by sarpogrelate and/or rosuvastatin treatment. The analysis of expression profiles at both the RNA and protein levels, using real-time quantitative polymerase chain reaction and Western blot analysis, indicated that LDL-R/CD68/LOX-1-positive monocyte/macrophage-mediated enhanced proinflammatory activation, including the significant upregulation of tumor necrosis factor-α and interleukin-6, was actually attenuated by sarpogrelate and/or rosuvastatin treatment. The findings indicated that sarpogrelate and/or rosuvastatin treatment potentially ameliorates CKD progression in patients with the aforementioned comorbid metabolic disorders.

Highlights

To date, the complex cellular and molecular nature of chronic kidney disease (CKD) has led to countless failures in clinical trials
The mice from the ApoE−/− HD group exhibited increased expression levels of CD68, which was almost reversed by rosuvastatin and/or sarpogrelate treatment in mice from the ApoE−/− HD+R or ApoE−/− HD+R+S group (∗P < 0:05 vs. ApoE−/− HD) (Figure 2(b)). These results suggested that rosuvastatin and sarpogrelate were involved in reducing the CD68-positive monocyte/macrophage-mediated proinflammatory activity induced by HD in ApoE-deficient mice
The results revealed a similar trend in some of these features compared with other methods used, the body weight was not affected under all the conditions and low-density lipoprotein (LDL)-c was even more increased in mice from the ApoE−/− HD+R group compared with mice from the ApoE−/− HD group (Table 2)

Summary

Introduction

The complex cellular and molecular nature of chronic kidney disease (CKD) has led to countless failures in clinical trials. Among the causative diseases of CKD, diabetes, hyperlipidemia, hypertension, and obesity have shown strong correlations with CKD [1,2,3,4,5,6]. Due to the diet and lifestyle in developed countries, most dyslipidemias turn out to be hyperlipidemias, that is, increased levels of apolipoproteins and low-density lipoprotein (LDL) cholesterol and decreased levels of high-density lipoprotein (HDL) cholesterol [1,2,3,4,5,6]. Selective alteration in the expression levels of ABCA1 and/or ApoE leads to increased susceptibility to atherosclerosis [9,10,11,12,13,14,15,16,17]

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