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

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.

Emerging Therapeutic Strategies for Attenuating Tubular EMT and Kidney Fibrosis by Targeting Wnt/β-Catenin Signaling

“…Depletion of kallistatin increased the levels of Wnt4, p-GSK3β (Ser9)/GSK3β, Axin2, active β-catenin, and target genes of Wnt/ β-catenin, whereas overexpression of kallistatin restrained the activation of Wnt/β-catenin. The regulatory effect of kallistatin on EMT and the activity of Wnt/β-catenin pathway in TGFβ1treated TECs was similar to that in vivo (Yiu et al, 2021).…”

Tumor Cell-Derived Exosomal miR-770 Inhibits M2 Macrophage Polarization via Targeting MAP3K1 to Inhibit the Invasion of Non-small Cell Lung Cancer Cells

“…Our study was similar to this previous research. β-catenin is known to be positively correlated with EMT process ( Li et al, 2021 ; Yiu et al, 2021 ). Therefore, the similar function between Wnt/β-catenin and tumor cell-derived exosomes might result in this similarity.…”

Tanshinone IIA attenuates high glucose-induced epithelial-to-mesenchymal transition in HK-2 cells through VDR/Wnt/β-catenin signaling pathway

“…In the study of Fu et al [31], the Wnt pathway was activated in the progression of EMT and tubulointerstitial lesions. Besides, kallistatin was proved to ameliorate EMT and renal fibrosis by inhibiting the Wnt pathway [32]. In normal condition, the complex in Wnt pathway, degrading βcatenin, is composed of adenomatosis polyposis coli (APC), axin and GSK-3β (Fig.…”