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

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