Blocking TGF-? and ?-Catenin Epithelial Crosstalk Exacerbates CKD.

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

SUBMITTER: Nlandu-Khodo S 

PROVIDER: S-EPMC5698068 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other