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

TitleProtective role of kallistatin in renal fibrosis via modulation of Wnt/β-catenin signaling
Authors
KeywordsBeta-catenin
Chronic kidney disease
Renal fibrosis
Fibroblasts
Fibroblasts
Issue Date2021
PublisherPortland Press Ltd. The Journal's web site is located at http://www.clinsci.org/
Citation
Clinical Science, 2021, v. 135 n. 3, p. 429-446 How to Cite?
AbstractKallistatin 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.
Persistent Identifierhttp://hdl.handle.net/10722/297163
ISSN
2021 Impact Factor: 6.876
2020 SCImago Journal Rankings: 1.910
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYiu, WH-
dc.contributor.authorLi, Y-
dc.contributor.authorLok, SWY-
dc.contributor.authorChan, KW-
dc.contributor.authorChan, LYY-
dc.contributor.authorLeung, JCK-
dc.contributor.authorLai, KN-
dc.contributor.authorTsu, JHL-
dc.contributor.authorChao, J-
dc.contributor.authorHuang, XR-
dc.contributor.authorLan, HY-
dc.contributor.authorTang, SCW-
dc.date.accessioned2021-03-08T07:15:03Z-
dc.date.available2021-03-08T07:15:03Z-
dc.date.issued2021-
dc.identifier.citationClinical Science, 2021, v. 135 n. 3, p. 429-446-
dc.identifier.issn0143-5221-
dc.identifier.urihttp://hdl.handle.net/10722/297163-
dc.description.abstractKallistatin 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.-
dc.languageeng-
dc.publisherPortland Press Ltd. The Journal's web site is located at http://www.clinsci.org/-
dc.relation.ispartofClinical Science-
dc.rightsThe final version of record is available at https://portlandpress.com/clinsci/article-abstract/135/3/429/227610/Protective-role-of-kallistatin-in-renal-fibrosis?redirectedFrom=fulltext-
dc.subjectBeta-catenin-
dc.subjectChronic kidney disease-
dc.subjectRenal fibrosis-
dc.subjectFibroblasts-
dc.subjectFibroblasts-
dc.titleProtective role of kallistatin in renal fibrosis via modulation of Wnt/β-catenin signaling-
dc.typeArticle-
dc.identifier.emailYiu, WH: whyiu@hku.hk-
dc.identifier.emailChan, KW: chriskwc@hku.hk-
dc.identifier.emailChan, LYY: yychanb@HKUCC-COM.hku.hk-
dc.identifier.emailLeung, JCK: jckleung@hku.hk-
dc.identifier.emailLai, KN: knlai@hku.hk-
dc.identifier.emailTsu, JHL: jamestsu@hku.hk-
dc.identifier.emailTang, SCW: scwtang@hku.hk-
dc.identifier.authorityLeung, JCK=rp00448-
dc.identifier.authorityLai, KN=rp00324-
dc.identifier.authorityTang, SCW=rp00480-
dc.description.naturepostprint-
dc.identifier.doi10.1042/CS20201161-
dc.identifier.pmid33458750-
dc.identifier.scopuseid_2-s2.0-85101568706-
dc.identifier.hkuros321496-
dc.identifier.volume135-
dc.identifier.issue3-
dc.identifier.spage429-
dc.identifier.epage446-
dc.identifier.isiWOS:000615903600001-
dc.publisher.placeUnited Kingdom-

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