| First Author | Hanna C | Year | 2013 |
| Journal | Am J Physiol Renal Physiol | Volume | 305 |
| Issue | 9 | Pages | F1323-31 |
| PubMed ID | 23946285 | Mgi Jnum | J:203002 |
| Mgi Id | MGI:5523749 | Doi | 10.1152/ajprenal.00155.2013 |
| Citation | Hanna C, et al. (2013) Hypoxia-inducible factor-2alpha and TGF-beta signaling interact to promote normoxic glomerular fibrogenesis. Am J Physiol Renal Physiol 305(9):F1323-31 |
| abstractText | Hypoxia-inducible factors (HIFs) are transcription factors consisting of an oxygen-sensitive alpha-subunit binding to a stable beta-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)-beta induction of collagen in renal tubular cells. Here, we performed in vitro and in vivo studies of potential glomerular crosstalk between TGF-beta and normoxic HIF signaling. HIF-alpha has two major isoforms, HIF-1alpha and HIF-2alpha with different target gene sets. In cultured human mesangial cells, TGF-beta1 treatment increased both HIF-1alpha and HIF-2alpha expression in normoxia. TGF-beta1 did not increase HIF-1alpha/2alpha mRNA levels nor decrease the rate of protein degradation, suggesting that it enhances HIF-1alpha/2alpha expression through translation. TGF-beta receptor (ALK5) kinase activity was required for increased, TGF-beta-stimulated HIF-alpha expression in response to TGF-beta, and inhibiting PI3-kinase markedly decreased HIF-alpha expression. Blocking HIF-1alpha/2alpha expression using siRNA decreased basal and TGF-beta1-stimulated type I collagen expression, while overexpressing nondegradable HIF-alpha increased the collagen response, with HIF-2alpha being significantly more effective than HIF-1alpha. In adriamycin-induced mouse glomerulosclerosis, HIF-2alpha target genes were upregulated in sclerosing glomeruli. Taken together, our data demonstrate potential signaling interaction between TGF-beta and HIFs to promote renal fibrogenesis in normoxia and suggest that the HIF-2alpha isoform is more important during glomerulosclerosis. |
