Regulation of hypoxia-inducible factor 2-a is essential for integrity of the glomerular barrier.
Deletion of the von Hippel-Lindau tumor suppressor (Vhl) gene from renal podocytes of mice (podVhl KO) leads to rapidly progressive glomerulonephritis (RPGN), a clinical syndrome characterized by rapid loss of renal function and crescents on renal biopsy. Genomic profiling of glomeruli isolated from podVhl knockout (KO) mice and from patients with RPGN identified a fingerprint of genes regulated by hypoxia-inducible factors (HIF), important substrates of the product of the VHL gene. Here, we show that stabilization of Hifs in podocytes is both required and sufficient for the glomerular phenotype observed in podVhl KO mice. Genetic deletion of the obligate dimerization partner Arnt/Hif1b that is essential for Hif transcriptional function rescues the phenotype. Conversely, stabilization of HIF2A alone in podocytes results in crescentic glomerular disease. Together, our results show that the Hif pathway and Hif2a in particular are key players in maintenance of the glomerular barrier.
Institute of Medicine Science, University of Toronto, Toronto, Canada.
Mei
M
Ding
Richard J
RJ
Coward
Marie
M
Jeansson
William
W
Kim
Susan E
SE
Quaggin
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D005921:Glomerulonephritis / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000502:physiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497396:ARNT protein, human; C497397:Arnt protein, mouse