Fibroblast-specific β-catenin signaling dictates the outcome of AKI

Dong Zhou, Haiyan Fu, Liangxiang Xiao, Hongyan Mo, Hui Zhuo, Xiaojun Tian, Lin Lin, Jianhua Xing, Youhua Liu

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

AKI is a devastating condition with high morbidity and mortality. The pathologic features of AKI are characterized by tubular injury, inflammation, and vascular impairment. Whether fibroblasts in the renal interstitium have a role in the pathogenesis of AKI is unknown. In this study, we investigated the role of fibroblast-specific β-catenin signaling in dictating the outcome of AKI, using conditional knockout mice in which β-catenin was specifically ablated in fibroblasts (Gli1-β-cat-/-). After ischemia-reperfusion injury (IRI), Gli1-β-cat-/-mice had lower serum creatinine levels and less morphologic injury than Gli1-β-cat+/+ littermate controls. Moreover, we detected fewer apoptotic cells, as well as decreased cytochrome C release; reduced expression of Bax, FasL, and p53; and increased phosphorylation of Akt, in the Gli1-β-cat-/- kidneys. Gli1-β-cat-/- kidneys also exhibited upregulated expression of proliferating cell nuclear antigen and Ki-67, which are markers of cell proliferation. Furthermore, Gli1-β-cat-/-kidneys displayed suppressed NF-κB signaling and cytokine expression and reduced infiltration of inflammatory cells. Notably, loss of β-catenin in fibroblasts induced renal expression of hepatocyte growth factor (HGF) and augmented the tyrosine phosphorylation of c-met receptor after IRI. In vitro, treatment with Wnt ligands or ectopic expression of active β-catenin inhibited HGF mRNA and protein expression and repressed HGF promoter activity. Collectively, these results suggest that fibroblast-specific β-catenin signaling can control tubular injury and repair in AKI by modulating HGF expression. Our studies uncover a previously unrecognized role for interstitial fibroblasts in the pathogenesis of AKI.

Original languageEnglish (US)
Pages (from-to)1257-1271
Number of pages15
JournalJournal of the American Society of Nephrology
Volume29
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

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Catenins
Cats
Hepatocyte Growth Factor
Fibroblasts
Kidney
Reperfusion Injury
Phosphorylation
Vascular System Injuries
Wounds and Injuries
Proliferating Cell Nuclear Antigen
Cytochromes
Knockout Mice
Tyrosine
Creatinine
Cell Proliferation
Cytokines
Ligands
Inflammation
Morbidity
Messenger RNA

ASJC Scopus subject areas

  • Nephrology

Cite this

Fibroblast-specific β-catenin signaling dictates the outcome of AKI. / Zhou, Dong; Fu, Haiyan; Xiao, Liangxiang; Mo, Hongyan; Zhuo, Hui; Tian, Xiaojun; Lin, Lin; Xing, Jianhua; Liu, Youhua.

In: Journal of the American Society of Nephrology, Vol. 29, No. 4, 01.04.2018, p. 1257-1271.

Research output: Contribution to journalArticle

Zhou, D, Fu, H, Xiao, L, Mo, H, Zhuo, H, Tian, X, Lin, L, Xing, J & Liu, Y 2018, 'Fibroblast-specific β-catenin signaling dictates the outcome of AKI', Journal of the American Society of Nephrology, vol. 29, no. 4, pp. 1257-1271. https://doi.org/10.1681/ASN.2017080903
Zhou, Dong ; Fu, Haiyan ; Xiao, Liangxiang ; Mo, Hongyan ; Zhuo, Hui ; Tian, Xiaojun ; Lin, Lin ; Xing, Jianhua ; Liu, Youhua. / Fibroblast-specific β-catenin signaling dictates the outcome of AKI. In: Journal of the American Society of Nephrology. 2018 ; Vol. 29, No. 4. pp. 1257-1271.
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