Hypoxia-inducible factor-1α promotes tubulointerstitial fibrosis via the upregulation of Muc4

Tubulointerstitial fibrosis (TIF) is the common final outcome of almost all progressive chronic kidney diseases (CKDs). Hypoxia-inducible factor-1 (HIF-1) activation plays an essential role in CKD; however, the specific contribution of tubular HIF-1 to renal TIF remains unclear. In the current study, the mechanism underlying HIF-1-mediated TIF was investigated. Intriguingly, we found that specifically knocking out HIF-1α in tubular cells attenuated unilateral ureteral obstruction-induced TIF, as shown by decreased accumulation of the extracellular matrix (ECM). Then, the results of transcriptomic analysis and in vivo and in vitro experiments revealed that expression of Mucin 4 (MUC4) was significantly decreased at the transcriptional and protein levels in tubular HIF-1α-knockout mice. Mechanistically, we demonstrated that HIF-1α directly bound to the Muc4 promoter and enhanced its transcription, as shown by chromatin immunoprecipitation and luciferase reporter assays. Moreover, RNA interference-mediated suppression of MUC4 significantly attenuated transforming growth factor-β induced ECM production by mouse tubular epithelial cells. Furthermore, MUC4 overexpression in the context of HIF-1α knockout was positively correlated with increased ECM protein expression and TIF. Altogether, these results demonstrate that tubular HIF-1α promotes TIF by upregulating Muc4 transcription. Our findings provide novel insights into the molecular mechanism underlying HIF-1-mediated TIF.