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

Wai Han Yiu, Ye Li, Sarah W. Y. Lok, Kam Wa Chan, Loretta Y. Y. Chan, Joseph C. K. Leung, Kar Neng Lai, James H. L. Tsu, Julie Chao, Xiao Ru Huang, Hui Yao Lan, Sydney C. W. Tang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

21 Citations (Scopus)

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 ofWnt4/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.

Original languageEnglish
Pages (from-to)429-446
Number of pages18
JournalClinical Science
Volume135
Issue number3
DOIs
Publication statusPublished - 1 Feb 2021

Scopus Subject Areas

  • Medicine(all)
  • Nephrology

User-Defined Keywords

  • beta-catenin
  • chronic kidney disease
  • fibroblasts
  • renal fibrosis

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