| First Author | Zhu F | Year | 2021 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1867 |
| Issue | 5 | Pages | 166081 |
| PubMed ID | 33486098 | Mgi Jnum | J:304089 |
| Mgi Id | MGI:6515381 | Doi | 10.1016/j.bbadis.2021.166081 |
| Citation | Zhu F, et al. (2021) Tubular Numb promotes renal interstitial fibrosis via modulating HIF-1alpha protein stability. Biochim Biophys Acta Mol Basis Dis 1867(5):166081 |
| abstractText | Tubulointerstitial fibrosis is the ultimate common pathway of all manners of chronic kidney disease. We previously demonstrated that specific deletion of Numb in proximal tubular cells (PTCs) prevented G2/M arrest and attenuated renal fibrosis. However, how Numb modulates cell cycle arrest remains unclear. Here, we showed that Numb overexpression significantly increased the protein level of hypoxia-inducible factor-1alpha (HIF-1alpha). Numb overexpression-induced G2/M arrest was blocked by silencing endogenous HIF-1alpha, subsequently downregulated the expression of cyclin G1 which is an atypical cyclin to promote G2/M arrest of PTCs. Further analysis revealed that Numb-augmented HIF-1alpha protein was blocked by simultaneously overexpressing MDM2. Moreover, silencing Numb decreased TGF-beta1-induceded HIF-1alpha protein expression. While endogenous MDM2 was knocked down this reduction was reversed, indicating that Numb stabilized HIF-1alpha protein via interfering MDM2-mediated HIF-1alpha protein degradation. Interestingly, HIF-1alpha overexpression significantly upregulated the expression of Numb and silencing endogenous HIF-1alpha blocked CoCl2 or TGF-beta1-induced Numb expression. Chromatin immunoprecipitation (ChIP) assays demonstrated that HIF-1alpha binded to the promoter region of Numb. This binding was significantly increased by TGF-beta1. Collectively, these data indicate that Numb and HIF-1alpha cooperates to promote G2/M arrest of PTCs, and thus aggravates tubulointerstitial fibrosis. Numb might be a potential target for the therapy of tubulointerstitial fibrosis. |
