Int J Biol Sci 2019; 15(1):239-252. doi:10.7150/ijbs.29063

Research Paper

Clopidogrel Reduces Fibronectin Accumulation and Improves Diabetes-Induced Renal Fibrosis

Zongyu Zheng1,2, Tianjiao Ma2,3, Xin Lian1, Jialin Gao1, Weigang Wang1, Wenya Weng2,4, Xuemian Lu4, Weixia Sun6, Yanli Cheng6, Yaowen Fu1✉, Madhavi J. Rane7, Evelyne Gozal2,5✉, Lu Cai2,5

1. Department of Urology, The First Hospital of Jilin University, Changchun 130021, China;
2. Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA;
3. Department of Rheumatology and Immunology, China-Japan Union Hospital of the Jilin University, Changchun 130033, China;
4. The Ruian Center of Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital of the Wenzhou Medical University, Ruian 325200, China.
5. Departments of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
6. Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, China.
7. Division of Nephrology, Department of Medicine, University of Louisville, Louisville, KY 40202, USA.

Abstract

Hyperglycemia-induced renal fibrosis causes end-stage renal disease. Clopidogrel, a platelet inhibitor, is often administered to decrease cardiovascular events in diabetic patients. We investigated whether clopidogrel can reduce diabetes-induced renal fibrosis in a streptozotocin-induced type 1 diabetes murine model and fibronectin involvement in this protective response. Diabetic and age-matched controls were sacrificed three months after the onset of diabetes, and additional controls and diabetic animals were further treated with clopidogrel or vehicle for three months. Diabetes induced renal morphological changes and fibrosis after three months. Clopidogrel, administered during the last three months, significantly decreased blood glucose, collagen and fibronectin expression compared to vehicle-treated diabetic mice. Diabetes increased TGF-β expression, inducing fibrosis via Smad-independent pathways, MAP kinases, and Akt activation at three months but returned to baseline at six months, whereas the expression of fibronectin and collagen remained elevated. Our results suggest that activation of TGF-β, CTGF, and MAP kinases are early profibrotic signaling events, resulting in significant fibronectin accumulation at the early time point and returning to baseline at a later time point. Akt activation at the three-month time point may serve as an adaptive response in T1D. Mechanisms of clopidogrel therapeutic effect on the diabetic kidney remain to be investigated as this clinically approved compound could provide novel approaches to prevent diabetes-induced renal disease, therefore improving patients' survival.

Keywords: Diabetes, clopidogrel, fibronectin (FN), renal fibrosis

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How to cite this article:
Zheng Z, Ma T, Lian X, Gao J, Wang W, Weng W, Lu X, Sun W, Cheng Y, Fu Y, Rane MJ, Gozal E, Cai L. Clopidogrel Reduces Fibronectin Accumulation and Improves Diabetes-Induced Renal Fibrosis. Int J Biol Sci 2019; 15(1):239-252. doi:10.7150/ijbs.29063. Available from http://www.ijbs.com/v15p0239.htm