p53 regulates renal expression of HIF-1{alpha} and pVHL under physiological conditions and after ischemia-reperfusion injury.
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-alpha 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-1alpha is principally expressed in the collecting tubules (CT) and thick ascending limbs (TAL) under physiological conditions. However, inhibition of p53 with pifithrin-alpha increases the faint expression of HIF-1alpha in proximal tubules (PT) under physiological conditions. Twenty-four hours after IRI, HIF-1alpha expression is decreased in both CT and TAL. HIF-1alpha expression in the PT is not significantly altered after IRI. Acute inhibition of p53 significantly increases HIF-1alpha expression in the PT after IRI. Additionally, pifithrin-alpha prevents the IRI-induced decrease in HIF-1alpha in the CT and TAL. Parallel changes are observed in the HIF-1alpha 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.
Sutton
Timothy A
TA
Div. of Nephrology, Dept. of Medicine, Indiana Univ. School of Medicine, 950 West Walnut St., R-II, 202, Indianapolis, IN 46202, USA. tsutton2@iupui.edu
Wilkinson
Jared
J
Mang
Henry E
HE
Knipe
Nicole L
NL
Plotkin
Zoya
Z
Hosein
Maya
M
Zak
Katelyn
K
Wittenborn
Jeremy
J
Dagher
Pierre C
PC
D058186:Acute Kidney Injury / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D002460:Cell Line; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007672:Kidney Cortex / Q000503:physiopathology; D007679:Kidney Medulla / Q000503:physiopathology; D007684:Kidney Tubules / Q000503:physiopathology; D008297:Male; D018613:Microscopy, Confocal; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
D052160:Benzothiazoles; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; D051794:Von Hippel-Lindau Tumor Suppressor Protein