Blocking TGF-β and β-Catenin Epithelial Crosstalk Exacerbates CKD

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