Contribution of Hypoxia inducible factor‐1α to the profibrotic action of angiotensin II in cultured renal medullary interstitial cells

Abstract

Hypoxia inducible factor (HIF)‐1α has been reported to promote fibrogenesis during the progression of chronic renal diseases. Although angiotensin II (ANG II) was shown to increase HIF‐1α levels in various renal cells, the role of HIF‐1α in ANG II‐induced profibrotic effect has not been determined. The present study was designed to test the hypothesis that HIF‐1α mediates profibrotic effect of ANG II. In cultured renal medullary interstitial cells (RMICs), ANG II (10−6 M) treatment for 20 hours doubled HIF‐1α mRNA levels, which was accompanied by the upregulation of proliferating cell nuclear antigen (PCNA), collagen I/III and tissue inhibitor of metalloproteinases (TIMP)‐1 by 69%, 65% and 26%, respectively. HIF‐1α siRNA decreased HIF‐1α mRNA levels by 60% and completely blocked ANG II‐induced increases in PCNA, collagen and TIMP‐1. Since transdifferentiation is implicated in ANG II‐induced renal tubulointerstitial injury, we also detected the expression of vimentin, a marker of transdifferentiation. It was demonstrated that HIF‐1α siRNA also abolished ANG II‐induced elevation of vimentin mRNA. Our data suggest that HIF‐1α may mediate ANG II‐induced renal fibrotic injury through activation of cell transdifferentiation. (Supported by NIH grant DK54927 and HL89563)