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p53 is renoprotective after ischemic kidney injury by reducing inflammation

Timothy A Sutton1, Takashi Hato, Erik Mai

  • 1Division of Nephrology, Department of Medicine, Indiana University, 950 W. Walnut Street, R2-202A, Indianapolis, IN 46202, USA.

Journal of the American Society of Nephrology : JASN
|December 11, 2012
PubMed

Insights

In mice, the absence of p53 (tumor protein 53) worsens kidney injury after ischemia. Leukocyte p53 is protective, reducing inflammation and promoting anti-inflammatory M2 macrophages.

Area of Science:

  • Nephrology
  • Immunology
  • Molecular Biology

Background:

  • The role of p53 in acute kidney injury (AKI) is complex, with conflicting evidence from rat models.
  • Pharmacologic inhibition of p53 shows acute protection but chronic enhancement of fibrosis in rats.

Purpose of the Study:

  • To investigate the role of genetic absence of p53 in ischemic AKI in mice.
  • To determine the specific contribution of leukocyte p53 to kidney injury and inflammation.

Main Methods:

  • Comparison of kidney injury in p53-knockout mice versus wild-type mice after ischemia.
  • Administration of pifithrin-α (p53 inhibitor) to wild-type mice.
  • Generation of chimeric mice lacking p53 in leukocytes.
  • Analysis of macrophage phenotype (M1/M2) and Kruppel-like factor-4 expression in kidney tissues.
  • Induction of peritonitis models to assess anti-inflammatory roles.

Main Results:

  • p53-knockout mice exhibited exacerbated kidney injury and prolonged leukocyte infiltration post-ischemia.
  • Acute p53 inhibition with pifithrin-α mimicked these detrimental effects.
  • Mice lacking p53 in leukocytes showed similar injury severity to p53-knockout mice.
  • Reduced M2 anti-inflammatory macrophage phenotype and Kruppel-like factor-4 expression were observed in p53-deficient kidneys.
  • p53 deficiency and inhibition impaired the anti-inflammatory response in peritonitis models.

Conclusions:

  • In contrast to rats, leukocyte p53 plays a protective role in murine ischemic AKI.
  • Leukocyte p53 mitigates kidney injury by reducing inflammation extent and duration.
  • p53 promotes the anti-inflammatory M2 macrophage phenotype, crucial for resolving inflammation.

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