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Activated renal tubular Wnt/?-catenin signaling triggers renal inflammation during overload proteinuria.

ABSTRACT: Imbalance of Wnt/?-catenin signaling in renal cells is associated with renal dysfunction, yet the precise mechanism is poorly understood. Previously we observed activated Wnt/?-catenin signaling in renal tubules during proteinuric nephropathy with an unknown net effect. Therefore, to identify the definitive role of tubular Wnt/?-catenin, we generated a novel transgenic "Tubcat" mouse conditionally expressing stabilized ?-catenin specifically in renal tubules following tamoxifen administration. Four weeks after tamoxifen injection, uninephrectomized Tubcat mice displayed proteinuria and elevated blood urea nitrogen levels compared to non-transgenic mice, implying a detrimental effect of the activated signaling. This was associated with infiltration of the tubulointerstitium predominantly by M1 macrophages and overexpression of the inflammatory chemocytokines CCL-2 and RANTES. Induction of overload proteinuria by intraperitoneal injection of low-endotoxin bovine serum albumin following uninephrectomy for four weeks aggravated proteinuria and increased blood urea nitrogen levels to a significantly greater extent in Tubcat mice. Renal dysfunction correlated with the degree of M1 macrophage infiltration in the tubulointerstitium and renal cortical up-regulation of CCL-2, IL-17A, IL-1?, CXCL1, and ICAM-1. There was overexpression of cortical TLR-4 and NLRP-3 in Tubcat mice, independent of bovine serum albumin injection. Finally, there was no fibrosis, activation of epithelial-mesenchymal transition or non-canonical Wnt pathways observed in the kidneys of Tubcat mice. Thus, conditional activation of renal tubular Wnt/?-catenin signaling in a novel transgenic mouse model demonstrates that this pathway enhances intrarenal inflammation via the TLR-4/NLRP-3 inflammasome axis in overload proteinuria.

SUBMITTER: Wong DWL

PROVIDER: S-EPMC5967994 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Activated renal tubular Wnt/β-catenin signaling triggers renal inflammation during overload proteinuria.

Wong Dickson W L DWL Yiu Wai Han WH Chan Kam Wa KW Li Ye Y Li Bin B Lok Sarah W Y SWY Taketo Makoto M MM Igarashi Peter P Chan Loretta Y Y LYY Leung Joseph C K JCK Lai Kar Neng KN Tang Sydney C W SCW

Kidney international 20180328 6

Imbalance of Wnt/β-catenin signaling in renal cells is associated with renal dysfunction, yet the precise mechanism is poorly understood. Previously we observed activated Wnt/β-catenin signaling in renal tubules during proteinuric nephropathy with an unknown net effect. Therefore, to identify the definitive role of tubular Wnt/β-catenin, we generated a novel transgenic "Tubcat" mouse conditionally expressing stabilized β-catenin specifically in renal tubules following tamoxifen administration. F ...[more]

PMID: 29605095

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Project description:Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-β1 (TGF-β1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16INK4a, p19ARF, and p21 expression and senescence-associated β-galactosidase (SA-β-gal) activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by small interfering RNA (siRNA)-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT-263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin (RAPA)-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1 (Baf A1)-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis.

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Activated renal tubular Wnt/?-catenin signaling triggers renal inflammation during overload proteinuria.

Publications

Activated renal tubular Wnt/β-catenin signaling triggers renal inflammation during overload proteinuria.

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