TY - JOUR
T1 - Fibroblast-specific β-catenin signaling dictates the outcome of AKI
AU - Zhou, Dong
AU - Fu, Haiyan
AU - Xiao, Liangxiang
AU - Mo, Hongyan
AU - Zhuo, Hui
AU - Tian, Xiaojun
AU - Lin, Lin
AU - Xing, Jianhua
AU - Liu, Youhua
N1 - Publisher Copyright:
© Copyright 2018 by the American Society of Nephrology.
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
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U2 - 10.1681/asn.2017080903
DO - 10.1681/asn.2017080903
M3 - Article
C2 - 29343518
AN - SCOPUS:85044717196
SN - 1046-6673
VL - 29
SP - 1257
EP - 1271
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 4
ER -