Hypoxia-inducible transcription factors and their role in renal disease.

ABSTRACT

The 2 hypoxia inducible factors (HIF)-1alpha and HIF-2alpha are key mediators of cellular adaptation to hypoxia. They show a specific distribution pattern and possibly have complementary transcriptional targets in the kidney HIF-1alpha is found mainly in tubular and HIF-2alpha in peritubular interstitial, endothelial, and glomerular cells. Both isoforms are regulated by oxygen-dependent hydroxylation of specific amino acid residues, which determines protein stability and transcriptional activity. Small molecule inhibitors of HIF hydroxylases act as pharmacologic inducers of HIF. HIF target genes are involved in cellular mechanisms that increase hypoxia tolerance or improve oxygen supply at the systemic or regional level, but also have been implicated in cellular apoptosis and profibrotic mechanisms. In experimental acute kidney injury the up-regulation of HIF either through endogenous hypoxia-sensing or after pharmacologic HIF stabilization confers tissue protection. Thus, HIF stabilization offers a promising novel and clinically feasible approach for nephroprotection. On the other hand, continuous activation of the HIF system occurs in kidney cancer and potentially promotes tumor growth. HIF therefore also is explored as a target for anticancer therapy.