Hypoxia induces ZEB2 in podocytes: Implications in the pathogenesis of proteinuria

Krishnamurthy Nakuluri, Dhanunjay Mukhi, Rajkishor Nishad, Moin A. Saleem, Sathish Kumar Mungamuri*, Ram K. Menon, Anil Kumar Pasupulati

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

9 Citations (Scopus)
281 Downloads (Pure)

Abstract

The glomerular filtration barrier (GFB) plays a critical role in ensuing protein free urine. The integrity of the GFB is compromised during hypoxia that prevails during extreme physiological conditions. However, the mechanism by which glomerular permselectivity is compromised during hypoxia remains enigmatic. Rats exposed to hypoxia showed a decreased glomerular filtration rate, podocyte foot-processes effacement, and proteinuria. Accumulation of hypoxia-inducible factor-1α (HIF1α) in podocytes resulted in elevated expression of zinc finger E-box binding homeobox 2 (ZEB2) and decreased expression of E- and P-cadherin. We also demonstrated that HIF1α binds to hypoxia response element localized in the ZEB2 promoter. Furthermore, HIF1α also induced the expression of ZEB2-natural antisense transcript, which is known to increase the efficiency of ZEB2 translation. Ectopic expression of ZEB2 induced loss of E- and P-cadherin and is associated with enhanced motility of podocytes during hypoxic conditions. ZEB2 knockdown abrogated hypoxia-induced decrease in podocyte permselectivity. This study suggests that hypoxia leads to activation of HIF1α–ZEB2 axis, resulting in podocyte injury and poor renal outcome.

Original languageEnglish
Pages (from-to)6503-6518
Number of pages16
JournalJournal of Cellular Physiology
Volume234
Issue number5
Early online date21 Sep 2018
DOIs
Publication statusPublished - May 2019

Keywords

  • HIF1α
  • hypoxia
  • podocyte
  • proteinuria
  • ZEB2.

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