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J Am Soc Nephrol. 2018 Apr;29(4):1257-1271. doi: 10.1681/ASN.2017080903. Epub 2018 Jan 17.

Fibroblast-Specific β-Catenin Signaling Dictates the Outcome of AKI.

Author information

1
Departments of Pathology and liuy@upmc.edu zhoudong@pitt.edu.
2
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
3
Departments of Pathology and.
4
Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.

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.

KEYWORDS:

HGF; Wnt; acute renal failure; apoptosis; fibroblast; signaling

PMID:
29343518
PMCID:
PMC5875957
DOI:
10.1681/ASN.2017080903
[Indexed for MEDLINE]
Free PMC Article

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