科研之友
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摘要
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-1 alpha (HIF-1 alpha). Numb overexpression-induced G2/M arrest was blocked by silencing endogenous HIF-1 alpha, 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-1 alpha protein was blocked by simultaneously overexpressing MDM2. Moreover, silencing Numb decreased TGF-beta 1-induceded HIF-1 alpha protein expression. While endogenous MDM2 was knocked down this reduction was reversed, indicating that Numb stabilized HIF-1 alpha protein via interfering MDM2mediated HIF-1 alpha protein degradation. Interestingly, HIF-1 alpha overexpression significantly upregulated the expression of Numb and silencing endogenous HIF-1 alpha blocked CoCl2 or TGF-beta 1-induced Numb expression. Chromatin immunoprecipitation (ChIP) assays demonstrated that HIF-1 alpha binded to the promoter region of Numb. This binding was significantly increased by TGF-beta 1. Collectively, these data indicate that Numb and HIF-1 alpha 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.
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单位南方医科大学
