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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.