Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice

ARTICLE HIGHLIGHTS

Research background

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease in the United States and most developed countries. New strategies are required to delay the development and the progression of DN.

Research motivation

Previous studies have shown that clopidogrel administration is an effective means of suppressing inflammation in diabetes. Moreover, clopidogrel can ameliorate diabetes-induced renal fibrosis in a streptozotocin-induced murine model of type 1 diabetes.

Research objectives

We aimed to determine whether treatment with clopidogrel has a preventive or therapeutic effect in the kidneys of obese type 2 diabetic db/db mice.

Research methods

Clopidogrel at doses of 5, 10, or 20 mg/kg was administered by gavage for 12 wk. The body mass, blood glucose, and urinary creatinine and albumin concentrations were measured. Immunohistochemistry, enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction were used to evaluate the expression of cytokines. Fibronectin (FN), and collagen I was assessed using immunohistochemistry.

Research results

Clopidogrel treatment reduced urinary albumin/creatinine ratio. Immunohistochemical staining revealed an amelioration of renal fibrosis, significantly less deposition of FN and collagen I. Lower expression of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β and lower levels of urinary TNF-α, monocyte chemoattractant protein-1 and significantly reduced macrophage infiltration of the db/db mice.

Research conclusions

Clopidogrel prevented renal dysfunction in db/db mice, most likely through inhibition of renal macrophage infiltration and the associated inflammation.

Research perspectives

The present findings suggest a promising alternative approach to the treatment of patients with diabetes and the prevention of DN because clopidogrel is in current use and could be co-administered with other antidiabetic drugs.