p53 regulates renal expression of HIF-1α and pVHL under physiological conditions and after ischemia-reperfusion injury

Timothy A. Sutton, Jared Wilkinson, Henry E. Mang, Nicole L. Knipe, Zoya Plotkin, Maya Hosein, Katelyn Zak, Jeremy Wittenborn, Pierre C. Dagher

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) and is characterized by widespread tubular and microvascular damage. The tumor suppressor p53 is upregulated after IRI and contributes to renal injury in part by promoting apoptosis. Acute, short-term inhibition of p53 with pifithrin-α conveys significant protection after IRI. The hypoxia-inducible factor-1 (HIF-1) pathway is also activated after IRI and has opposing effects to those promoted by p53. The balance between the HIF-1 and p53 responses can determine the outcome of IRI. In this manuscript, we investigate whether p53 regulates the HIF-1 pathway in a rodent model of IRI. HIF-1α is principally expressed in the collecting tubules (CT) and thick ascending limbs (TAL) under physiological conditions. However, inhibition of p53 with pifithrin-α increases the faint expression of HIF-1α in proximal tubules (PT) under physiological conditions. Twenty-four hours after IRI, HIF-1α expression is decreased in both CT and TAL. HIF-1α expression in the PT is not significantly altered after IRI. Acute inhibition of p53 significantly increases HIF-1α expression in the PT after IRI. Additionally, pifithrin-α prevents the IRI-induced decrease in HIF-1α in the CT and TAL. Parallel changes are observed in the HIF-1α transcriptive target, carbonic anhydrase-9. Finally, inhibition of p53 prevents the dramatic changes in Von Hippel-Lindau protein morphology and expression after IRI. We conclude that activation of p53 after IRI mitigates the concomitant activation of the protective HIF-1 pathway. Modulating the interactions between the p53 and HIF-1 pathway can provide novel options in the treatment of AKI.

Original languageEnglish (US)
Pages (from-to)F1666-F1677
JournalAmerican Journal of Physiology - Renal Physiology
Volume295
Issue number6
DOIs
StatePublished - Dec 1 2008

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Keywords

  • Acute kidney injury
  • Acute renal failure
  • Hypoxia-inducible factor-1α
  • Von Hippel-Lindau protein

ASJC Scopus subject areas

  • Physiology
  • Urology

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