Hypoxia-inducible factor-2α and TGF-β signaling interact to promote normoxic glomerular fibrogenesis

Christian Hanna, Susan C. Hubchak, Xiaoyan Liang, Benaya Rozen-Zvi, Paul T. Schumacker, Tomoko Hayashida, H. William Schnaper*

*Corresponding author for this work

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Hypoxia-inducible factors (HIFs) are transcription factors consisting of an oxygen-sensitive α-subunit binding to a stable β-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)-β induction of collagen in renal tubular cells. Here, we performed in vitro and in vivo studies of potential glomerular crosstalk between TGF-β and normoxic HIF signaling. HIF-α has two major isoforms, HIF-1α and HIF-2α with different target gene sets. In cultured human mesangial cells, TGF-β1 treatment increased both HIF-1α and HIF-2α expression in normoxia. TGF-β1 did not increase HIF-1α/2α mRNA levels nor decrease the rate of protein degradation, suggesting that it enhances HIF-1α/2α expression through translation. TGF-β receptor (ALK5) kinase activity was required for increased, TGF-β-stimulated HIF-α expression in response to TGF-β, and inhibiting PI3-kinase markedly decreased HIF-α expression. Blocking HIF-1α/2α expression using siRNA decreased basal and TGF-β1-stimulated type I collagen expression, while overexpressing nondegradable HIF-α increased the collagen response, with HIF-2α being significantly more effective than HIF-1α. In adriamycin-induced mouse glomerulosclerosis, HIF-2α target genes were upregulated in sclerosing glomeruli. Taken together, our data demonstrate potential signaling interaction between TGF-β and HIFs to promote renal fibrogenesis in normoxia and suggest that the HIF-2α isoform is more important during glomerulosclerosis.

Original languageEnglish (US)
Pages (from-to)F1323-F1331
JournalAmerican Journal of Physiology - Renal Physiology
Volume305
Issue number9
DOIs
StatePublished - Nov 1 2013

Keywords

  • Collagen
  • Fibrosis
  • HIF
  • TGF-β

ASJC Scopus subject areas

  • Physiology
  • Urology

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