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

Abstract

<p class="first" id="P1">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 <i>vs.</i> damage?). 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. Four weeks after tamoxifen injection, uninephrectomized Tubcat mice displayed proteinuria and elevated BUN levels comparing to non-transgenic mice, 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, after uninephrectomy, 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. There was overexpression of cortical TLR-4 and NLRP-3 in Tubcat mice, independent of BSA injection. Finally, there is no fibrosis formation or activation of epithelial-mesenchymal-transition or non-canonical Wnt pathways being observed in the Tubcat kidney. In conclusion, conditional activation of renal tubular Wnt/β-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. </p>