Blocking TGF-<i>β</i> and <i>β</i>-Catenin Epithelial Crosstalk Exacerbates CKD.

Abstract

The TGF-<i>β</i> and Wnt/<i>β</i>-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF-<i>β</i> has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF-<i>β</i> signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF-<i>β</i> type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF-<i>β</i> receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF-<i>β</i> receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/<i>β</i>-catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF-<i>β</i> receptor impaired <i>β</i>-catenin activity <i>in vitro</i> and <i>in vivo</i> Genetically restoring <i>β</i>-catenin activity in proximal tubules lacking the TGF-<i>β</i> receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF-<i>β</i> receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of <i>β</i>-catenin activity or an indirect effect of <i>β</i>-catenin interacting with other growth factors. In conclusion, blocking TGF-<i>β</i> and <i>β</i>-catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD.