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Biochim Biophys Acta Gen Subj. 2019 Jul;1863(7):1210-1216. doi: 10.1016/j.bbagen.2019.04.016. Epub 2019 Apr 24.

Tauroursodeoxycholic acid attenuates cyclosporine-induced renal fibrogenesis in the mouse model.

Author information

1
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
2
National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan 430068, China.
3
Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
4
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
5
Departments of Pediatrics & Physiology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
6
School of Human Nutrition, McGill University, Ste. Anne de Bellevue, Quebec H9X 3V9, Canada. Electronic address: luis.agellon@mcgill.ca.
7
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Electronic address: marek.michalak@ualberta.ca.

Abstract

Chronic exposure to cyclosporine causes nephrotoxicity and organ damage. Here we show that cyclosporine nephrotoxicity in vivo is associated with the activation of the unfolded protein response (UPR) pathway to initiate tissue fibrosis. We demonstrate that cyclosporine therapy activated the IRE1α branch of the unfolded protein response (UPR) and stimulated the TGFβ1 signaling pathway in the kidneys of male mice. Co-administration of the proteostasis promoter tauroursodeoxycholic acid (TUDCA) with cyclosporine inhibited the UPR pathway in the kidneys of treated male mice as well as decreased the development of renal fibrogenesis.

KEYWORDS:

Cyclosporine; Fibrogenesis; Kidney disease; Proteostasis promoter; TUDCA; Unfolded protein responses

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