摘要
BACKGROUND Diabetic nephropathy(DN)is the principal cause of end-stage renal disease.Previous studies have shown that clopidogrel can prevent the early progression of renal injury.AIM To elucidate whether clopidogrel is beneficial against DN by using a db/db mouse model.METHODS db/db mice with a higher urinary albumin/creatinine ratio(ACR)relative to ageand sex-matched wild-type control mice were randomly allocated to clopidogrel and vehicle treatment groups.Clopidogrel was administered at doses of 5,10,and 20 mg/kg by gavage for 12 wk.Body mass,blood glucose level,and urinary creatinine and albumin concentrations in each group were measured before and after the intervention.Renal fibrosis was evaluated using periodic acid-Schiff and Masson’s trichrome staining.The renal protein expression of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),and F4/80 was assessed using immunohistochemistry.Urinary TNF-α,monocyte chemoattractant protein-1(MCP-1),and IL-6 levels were analyzed using enzyme-linked immunosorbent assay;TNF-αand IL-1βmRNA expression was measured using real-time quantitative polymerase chain reaction.The protein expression of fibronectin(FN)and collagen I was assessed using immunohistochemistry.RESULTS Clopidogrel treatment did not affect the body mass or blood glucose level of the db/db mice;however,it increased bleeding time and reduced urinary ACR in a dose-dependent manner.Immunohistochemical staining revealed an amelioration of renal fibrosis,significantly lower deposition of FN and collagen I,and significantly lower expression of the proinflammatory cytokines TNF-αand IL-1βand lower levels of urinary TNF-αand MCP-1 in the clopidogrel-treated db/db mice(P<0.05).Furthermore,clopidogrel significantly reduced macrophage infiltration into the glomeruli of the db/db mice.CONCLUSION Clopidogrel significantly reduced renal collagen deposition and fibrosis and prevented renal dysfunction in db/db mice,most likely through inhibition of renal macrophage infiltration and the associated inflammation.
作者简介
Corresponding author:Jin Pei,PhD,Professor,Department of Biopharmacy,Jilin University School of Pharmaceutical Sciences,No.1163,Xinmin street,Changchun 130021,Jilin Province,China.peijin@jlu.edu.cn。
