TY - JOUR
T1 - Blocking TGF-β and -β-catenin epithelial crosstalk exacerbates CKD
AU - Nlandu-Khodo, Stellor
AU - Neelisetty, Surekha
AU - Phillips, Melanie
AU - Manolopoulou, Marika
AU - Bhave, Gautam
AU - May, Lauren
AU - Clark, Peter E.
AU - Yang, Haichun
AU - Fogo, Agnes B.
AU - Harris, Raymond C.
AU - Taketo, M. Mark
AU - Lee, Ethan
AU - Gewin, Leslie S.
N1 - Funding Information:
This work was supported by an American Heart Association Postdoctoral Fellowship award (to S.N.-K.); a National Research Service Award Institutional Research Training Grant T32 (to M.M.); National Institutes of Health (NIH) grants K08DK097306 (to G.B.), 1R35GM122516-01 (to E.L.), and R01DK108968-01 (to L.S.G.); Burroughs–Wellcome Fund Career Award for Medical Scientists 13030995 (to G.B.); and a Career Development Award from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (to L.S.G.). VANTAGE is supported, in part, by Clinical and Translational Science Awards (CTSA) grant 5UL1 RR024975-03, Vanderbilt Ingram Cancer Center grant P30 CA68485, Vanderbilt Vision Center grant P30 EY08126, and NIH/National Center for Research Resources (NCRR) grant G20 RR030956. The VMC Flow Cytometry Shared Resource is supported by Vanderbilt Ingram Cancer Center grant P30 CA68485 and Vanderbilt Digestive Disease Research Center grant DK058404.
PY - 2017/12
Y1 - 2017/12
N2 - 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 thepathwaymost affected.We validatedthatdeletingtheproximal tubularTGF-β receptor impairedβ-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 toCKDinmice. Deleting the TGF-β receptor altersmany 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.
AB - 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 thepathwaymost affected.We validatedthatdeletingtheproximal tubularTGF-β receptor impairedβ-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 toCKDinmice. Deleting the TGF-β receptor altersmany 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.
UR - https://www.scopus.com/pages/publications/85038430271
U2 - 10.1681/ASN.2016121351
DO - 10.1681/ASN.2016121351
M3 - Article
C2 - 28701516
AN - SCOPUS:85038430271
SN - 1046-6673
VL - 28
SP - 3490
EP - 3503
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -