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

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 -catenin signaling in dictating the outcome of AKI, using conditional knockout mice in which-catenin was specifically ablated in fibroblasts (Gli1--cat-/-). After ischemia-reperfusion injury (IRI), Gli1--cat-/- mice had lower serum creatinine levels and less morphologic injury than Gli1--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--cat-/- kidneys. Gli1--cat-/- kidneys also exhibited upregulated expression of proliferating cell nuclear antigen and Ki-67, which are markers of cell proliferation. Furthermore, Gli1--cat-/- kidneys displayed suppressed NF-κB signaling and cytokine expression and reduced infiltration of inflammatory cells. Notably, loss of -catenin in fibroblasts induced renal expression of hepatocyte growth factor (HGF) and augmented the tyrosine phosphorylation of c-met receptor after IRI., treatment with Wnt ligands or ectopic expression of active -catenin inhibited HGF mRNA and protein expression and repressed HGF promoter activity. Collectively, these results suggest that fibroblast-specific-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.

The MicroRNA MiR-29c Alleviates Renal Fibrosis via TPM1-Mediated Suppression of the Wnt/β-Catenin Pathway

“…We have confirmed that the expression of HGF, a known Wnt/β-catenin-targeted gene (Zhou et al, 2018), was restored after overexpression of miR-29c in TGF-β1-treated NRK-49F cells and UUO mouse kidneys. As a potent anti-fibrotic factor, HGF both antagonizes the action of TGF-β1 and represses renal inflammation (Liu, 2004;Giannopoulou et al, 2008).…”

“…At present, the mechanism by which miR-29c downregulates TGF-β1 remains unclear. As miR-29c action is associated with HGF, a potent anti-fibrotic factor that antagonizes TGF-β1 activity (Giannopoulou et al, 2008;Zhou et al, 2018), repression of TGF-β1 by miR-29c may be mediated by HGF; more research is required to test this hypothesis.…”

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

“…β‐catenin is the downstream effector of Wnt signalling in tubular cell senescence, podocyte dedifferentiation and fibroblast activation . Although β‐catenin expression is silent in normal adult kidneys, it is reactivated at an early stage and keeps activation in the progression of CKD .…”

Expression Profiling of Fibroblasts in Chronic and Acute Disease Models Reveals Novel Pathways in Kidney Fibrosis

“…Consistent with our data, genetic fibroblast-specific ablation of b-catenin, the canonical WNT signaling effector, results in less injury and inflammation after renal ischemia, suggesting that increased WNT signaling in activated fibroblasts inhibits tubular repair and promotes immune cell infiltration. 23 Many of these pathways have previously been identified in animal models of renal injury and fibrosis using other methods, such as sophisticated genetic labeling of different cell populations, 24,25 demonstrating that FACS for PDGFra + cells is a viable alternative to genetic lineage markers for fibroblasts.…”