Activated Renal Tubular Wnt/β-Catenin Signaling Triggers Renal Inflammation during Proteinuria

Abstract

Background: 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 (rescue vs. damage?) (Cell Death Dis 2016; 24;7:e2155). Methods: To identify the definitive role of tubular Wnt/β-catenin, we generated a novel transgenic “Tubcat” mouse, which conditionally expresses stabilized β-catenin specifically in renal tubules after tamoxifen administration. Results: Four weeks after tamoxifen induction, Tubcat mice displayed proteinuria and elevated BUN levels, implying a detrimental effect of the activated signaling. This was associated with tubulointerstitial infiltration predominantly by M1 macrophages and overexpression of the inflammatory chemocytokines CCL-2 and RANTES. Induction of overload proteinuria by low-endotoxin BSA injection for 4 weeks aggravated proteinuria and increased BUN 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-1β, CXCL1 and ICAM-1. Finally, there was overexpression of cortical TLR-4 and NLRP-3 in Tubcat mice, irrespective of BSA injection. Conclusions: Conditional activation of renal tubular Wnt/β-catenin signaling enhances intrarenal inflammation via the TLR-4/NLRP-3 inflammasome axis in overload proteinuria. Funding support: National Natural Science Fund (NSFC) of China (grant no. 81570647)