Blocking TGF-and-Catenin Epithelial Crosstalk Exacerbates CKD.
AUTHORS
- PMID: 28701516 [PubMed].
- PMCID: PMC5698068.
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 activityandGenetically 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.
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 activityandGenetically 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.
Tags: 2017