Hypoxia-inducible factor-2α and TGF-β signaling interact to promote normoxic glomerular fibrogenesis.
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.
Morton 4-685G (MS# W-140 310 E. Superior St., Chicago, IL 60611-3008. schnaper@northwestern.edu.
Christian
C
Hanna
Susan C
SC
Hubchak
Xiaoyan
X
Liang
Benaya
B
Rozen-Zvi
Paul T
PT
Schumacker
Tomoko
T
Hayashida
H William
HW
Schnaper
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D005355:Fibrosis; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D010100:Oxygen; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D003094:Collagen; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
HIF; TGF-β; collagen; fibrosis