Protective role of kallistatin in renal fibrosis via modulation of Wnt/β-catenin signaling

Author:

Yiu Wai Han1,Li Ye1,Lok Sarah W.Y.1,Chan Kam Wa1,Chan Loretta Y.Y.1,Leung Joseph C.K.1,Lai Kar Neng1,Tsu James H.L.2,Chao Julie3,Huang Xiao-Ru4,Lan Hui Yao4,Tang Sydney C.W.1ORCID

Affiliation:

1. Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong

2. Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong

3. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, U.S.A.

4. Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong

Abstract

Abstract Kallistatin is a multiple functional serine protease inhibitor that protects against vascular injury, organ damage and tumor progression. Kallistatin treatment reduces inflammation and fibrosis in the progression of chronic kidney disease (CKD), but the molecular mechanisms underlying this protective process and whether kallistatin plays an endogenous role are incompletely understood. In the present study, we observed that renal kallistatin levels were significantly lower in patients with CKD. It was also positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with serum creatinine level. Unilateral ureteral obstruction (UUO) in animals also led to down-regulation of kallistatin protein in the kidney, and depletion of endogenous kallistatin by antibody injection resulted in aggravated renal fibrosis, which was accompanied by enhanced Wnt/β-catenin activation. Conversely, overexpression of kallistatin attenuated renal inflammation, interstitial fibroblast activation and tubular injury in UUO mice. The protective effect of kallistatin was due to the suppression of TGF-β and β-catenin signaling pathways and subsequent inhibition of epithelial-to-mesenchymal transition (EMT) in cultured tubular cells. In addition, kallistatin could inhibit TGF-β-mediated fibroblast activation via modulation of Wnt4/β-catenin signaling pathway. Therefore, endogenous kallistatin protects against renal fibrosis by modulating Wnt/β-catenin-mediated EMT and fibroblast activation. Down-regulation of kallistatin in the progression of renal fibrosis underlies its potential as a valuable clinical biomarker and therapeutic target in CKD.

Publisher

Portland Press Ltd.

Subject

General Medicine

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