Ethan Lee
Faculty Member
Last active: 7/23/2019

Blocking TGF- and -Catenin Epithelial Crosstalk Exacerbates CKD.

Nlandu-Khodo S, Neelisetty S, Phillips M, Manolopoulou M, Bhave G, May L, Clark PE, Yang H, Fogo AB, Harris RC, Taketo MM, Lee E, Gewin LS
J Am Soc Nephrol. 2017 28 (12): 3490-3503

PMID: 28701516 · PMCID: PMC5698068 · DOI:10.1681/ASN.2016121351

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 and 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.

Copyright © 2017 by the American Society of Nephrology.

MeSH Terms (22)

Animals Aristolochic Acids beta Catenin Cell Nucleus Collagen Crosses, Genetic Epithelium Female Gene Deletion Kidney Failure, Chronic Kidney Tubules, Proximal Male Mice Mice, Inbred BALB C Mice, Knockout Mice, Transgenic Protein-Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta Signal Transduction Transforming Growth Factor beta1 Wnt Proteins

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