Regulation of Hypoxia -Inducible Factor 2-Alpha is Essential for Integrity of the Glomerular Barrier

Mei Ding, Richard John Mark Coward, Marie Jeansson, William Kim, Susan E Quaggin

Research output: Contribution to journalArticle (Academic Journal)

7 Citations (Scopus)

Abstract

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 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 Hif's 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.
Original languageEnglish
Pages (from-to)F120-F126
JournalAJP - Renal Physiology
Volume304
DOIs
Publication statusPublished - 2013

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  • Projects

    MRC Award

    Coward , R. J. M.

    1/12/061/12/10

    Project: Research

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