Journal
CLINICAL SCIENCE
Volume 135, Issue 3, Pages 429-446Publisher
PORTLAND PRESS LTD
DOI: 10.1042/CS20201161
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Funding
- Research Grants Council of Hong Kong [17151716, 17119818, C7018-16G]
- Health and Medical Research Fund (HMRF) of Hong Kong [05163596]
- Hong Kong Society of Nephrology/Hong Kong Kidney Foundation Research Grant 2017
- University of Hong Kong
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Kallistatin acts as a protective factor against renal fibrosis in chronic kidney disease by modulating Wnt/beta-catenin-mediated EMT and fibroblast activation. Its down-regulation in CKD progression suggests its potential as a valuable clinical biomarker and therapeutic target.
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/beta-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-beta and beta-catenin signaling pathways and subsequent inhibition of epithelial-to-mesenchymal transition (EMT) in cultured tubular cells. In addition, kallistatin could inhibit TGF-beta-mediated fibroblast activation via modulation of Wnt4/beta-catenin signaling pathway. Therefore, endogenous kallistatin protects against renal fibrosis by modulating Wnt/beta-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.
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