期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 28, 期 12, 页码 3490-3503出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2016121351
关键词
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资金
- American Heart Association
- National Research Service Award Institutional Research Training Grant T32
- National Institutes of Health (NIH) [K08DK097306, 1R35GM122516-01, R01DK108968-01]
- Burroughs-Wellcome Fund Career Award for Medical Scientists [13030995]
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development
- Clinical and Translational Science Awards (CTSA) [5UL1 RR024975-03]
- Vanderbilt Ingram Cancer Center [P30 CA68485]
- Vanderbilt Vision Center [P30 EY08126]
- NIH/National Center for Research Resources (NCRR) [G20 RR030956]
- Vanderbilt Digestive Disease Research Center [DK058404]
The TGF-beta and Wnt/beta-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF-beta has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF-beta signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF-beta type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF-beta receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF-beta receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/beta-catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF-beta receptor impaire db-catenin activity in vitro and in vivo. Genetically restoring beta-catenin activity in proximal tubules lacking the TGF-beta receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF-beta receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of b-catenin activity or an indirect effect of beta-catenin interacting with other growth factors. In conclusion, blocking TGF-beta and beta-catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD.
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