Regulation of hypoxia-inducible factor 2-a is essential for integrity of the glomerular barrier

Mei Ding, Richard J. Coward, Marie Jeansson, William Kim, Susan E. Quaggin

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)F120-F126
JournalAmerican Journal of Physiology - Renal Physiology
Volume304
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Glomerular barrier
  • Hypoxia-inducible factors
  • Rapidly progressive glomerulonephritis

ASJC Scopus subject areas

  • Physiology
  • Urology

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