Hypoxia-inducible factor-2? and TGF-? signaling interact to promote normoxic glomerular fibrogenesis.

ABSTRACT: Hypoxia-inducible factors (HIFs) are transcription factors consisting of an oxygen-sensitive ?-subunit binding to a stable ?-subunit. HIFs regulate multiple signaling pathways that could contribute to fibrogenesis, supporting their potential role in hypoxia-mediated renal fibrosis. We previously reported that HIF-1 is upregulated and required for transforming growth factor (TGF)-? induction of collagen in renal tubular cells. Here, we performed in vitro and in vivo studies of potential glomerular crosstalk between TGF-? and normoxic HIF signaling. HIF-? has two major isoforms, HIF-1? and HIF-2? with different target gene sets. In cultured human mesangial cells, TGF-?1 treatment increased both HIF-1? and HIF-2? expression in normoxia. TGF-?1 did not increase HIF-1?/2? mRNA levels nor decrease the rate of protein degradation, suggesting that it enhances HIF-1?/2? expression through translation. TGF-? receptor (ALK5) kinase activity was required for increased, TGF-?-stimulated HIF-? expression in response to TGF-?, and inhibiting PI3-kinase markedly decreased HIF-? expression. Blocking HIF-1?/2? expression using siRNA decreased basal and TGF-?1-stimulated type I collagen expression, while overexpressing nondegradable HIF-? increased the collagen response, with HIF-2? being significantly more effective than HIF-1?. In adriamycin-induced mouse glomerulosclerosis, HIF-2? target genes were upregulated in sclerosing glomeruli. Taken together, our data demonstrate potential signaling interaction between TGF-? and HIFs to promote renal fibrogenesis in normoxia and suggest that the HIF-2? isoform is more important during glomerulosclerosis.

SUBMITTER: Hanna C 

PROVIDER: S-EPMC3840227 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature