| First Author | Nlandu-Khodo S | Year | 2017 |
| Journal | J Am Soc Nephrol | Volume | 28 |
| Issue | 12 | Pages | 3490-3503 |
| PubMed ID | 28701516 | Mgi Jnum | J:274985 |
| Mgi Id | MGI:6295324 | Doi | 10.1681/ASN.2016121351 |
| Citation | Nlandu-Khodo S, et al. (2017) Blocking TGF-beta and beta-Catenin Epithelial Crosstalk Exacerbates CKD. J Am Soc Nephrol 28(12):3490-3503 |
| abstractText | 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 impaired beta-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 beta-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. |
