p53 is renoprotective after ischemic kidney injury by reducing inflammation

Timothy Sutton, Takashi Hato, Erik Mai, Momoko Yoshimoto, Sarah Kuehl, Melissa Anderson, Henry Mang, Zoya Plotkin, Rebecca Chan, Pierre Dagher

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

In the rat, p53 promotes tubular apoptosis after ischemic AKI. Acute pharmacologic inhibition of p53 is protective in this setting, but chronic inhibition enhances fibrosis, demonstrating that the role of p53 in ischemic AKI is incompletely understood. Here, we investigated whether genetic absence of p53 is also protective in ischemic AKI. Surprisingly, p53-knockout mice (p53-/-) had worse kidney injury, compared with wild-type mice, and exhibited increased and prolonged infiltration of leukocytes after ischemia. Acute inhibition of p53 with pifithrin-a in wild-type mice mimicked the observations in p53-/- mice. Chimeric mice that lacked p53 in leukocytes sustained injury similar to p53-/- mice, suggesting an important role for leukocyte p53 in ischemic AKI. Compared with wild-type mice, a smaller proportion of macrophages in the kidneys of p53-/- and pifithrin-α-treated mice after ischemic injury were the anti-inflammatory M2 phenotype. Ischemic kidneys of p53-/- and pifithrin-α- treated mice also showed reduced expression of Kruppel-like factor-4. Finally, models of peritonitis in p53-/- and pifithrin-a-treated mice confirmed the anti-inflammatory role of p53 and its effect on the polarization of macrophage phenotype. In summary, in contrast to the rat, inflammation characterizes ischemic AKI in mice; leukocyte p53 is protective by reducing the extent and duration of this inflammation and by promoting the anti-inflammatory M2 macrophage phenotype.

Original languageEnglish
Pages (from-to)113-124
Number of pages12
JournalJournal of the American Society of Nephrology
Volume24
Issue number1
DOIs
StatePublished - Dec 28 2013

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Inflammation
Kidney
Wounds and Injuries
Leukocytes
Anti-Inflammatory Agents
Macrophages
Phenotype
Peritonitis
Knockout Mice
Fibrosis
Ischemia
Apoptosis
pifithrin

ASJC Scopus subject areas

  • Nephrology

Cite this

p53 is renoprotective after ischemic kidney injury by reducing inflammation. / Sutton, Timothy; Hato, Takashi; Mai, Erik; Yoshimoto, Momoko; Kuehl, Sarah; Anderson, Melissa; Mang, Henry; Plotkin, Zoya; Chan, Rebecca; Dagher, Pierre.

In: Journal of the American Society of Nephrology, Vol. 24, No. 1, 28.12.2013, p. 113-124.

Research output: Contribution to journalArticle

Sutton, Timothy ; Hato, Takashi ; Mai, Erik ; Yoshimoto, Momoko ; Kuehl, Sarah ; Anderson, Melissa ; Mang, Henry ; Plotkin, Zoya ; Chan, Rebecca ; Dagher, Pierre. / p53 is renoprotective after ischemic kidney injury by reducing inflammation. In: Journal of the American Society of Nephrology. 2013 ; Vol. 24, No. 1. pp. 113-124.
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