title: p53 is renoprotective after ischemic kidney injury by reducing inflammation.
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-α 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-α-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.
authors.affiliation: Division of Nephrology, Department of Medicine, Indiana University, 950 W. Walnut Street, R2-202A, Indianapolis, IN 46202, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Sutton
authors.forename: Takashi
authors.initials: T
authors.lastname: Hato
authors.forename: Erik
authors.initials: E
authors.lastname: Mai
authors.forename: Momoko
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Sarah
authors.initials: S
authors.lastname: Kuehl
authors.forename: Melissa
authors.initials: M
authors.lastname: Anderson
authors.forename: Henry
authors.initials: H
authors.lastname: Mang
authors.forename: Zoya
authors.initials: Z
authors.lastname: Plotkin
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
authors.forename: Pierre C
authors.initials: PC
authors.lastname: Dagher
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D052160:Benzothiazoles; D016026:Bone Marrow Transplantation; D002678:Chimera; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D010538:Peritonitis / Q000378:metabolism; D010641:Phenotype; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014050:Toluene / Q000031:analogs & derivatives; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D016207:Cytokines; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin