Targeted deletion of p53 in the proximal tubule prevents ischemic renal injury.
The contribution of p53 to kidney dysfunction, inflammation, and tubular cell death, hallmark features of ischemic renal injury (IRI), remains undefined. Here, we studied the role of proximal tubule cell (PTC)-specific p53 activation on the short- and long-term consequences of renal ischemia/reperfusion injury in mice. After IRI, mice with PTC-specific deletion of p53 (p53 knockout [KO]) had diminished whole-kidney expression levels of p53 and its target genes, improved renal function, which was shown by decreased plasma levels of creatinine and BUN, and attenuated renal histologic damage, oxidative stress, and infiltration of neutrophils and macrophages compared with wild-type mice. Notably, necrotic cell death was attenuated in p53 KO ischemic kidneys as well as oxidant-injured p53-deficient primary PTCs and pifithrin-α-treated PTC lines. Reduced oxidative stress and diminished expression of PARP1 and Bax in p53 KO ischemic kidneys may account for the decreased necrosis. Apoptosis and expression of proapoptotic p53 targets, including Bid and Siva, were also significantly reduced, and cell cycle arrest at the G2/M phase was attenuated in p53 KO ischemic kidneys. Furthermore, IRI-induced activation of TGF-β and the long-term development of inflammation and interstitial fibrosis were significantly reduced in p53 KO mice. In conclusion, specific deletion of p53 in the PTC protects kidneys from functional and histologic deterioration after IRI by decreasing necrosis, apoptosis, and inflammation and modulates the long-term sequelae of IRI by preventing interstitial fibrogenesis.
Departments of Cellular and Integrative Physiology and.
Yuan
Y
Ying
Departments of Cellular and Integrative Physiology and Department of Anatomy, Jeju National University School of Medicine, Jeju, Republic of Korea.
Jinu
J
Kim
Departments of Cellular and Integrative Physiology and.
Sherry N
SN
Westphal
Departments of Cellular and Integrative Physiology and.
Kelly E
KE
Long
Departments of Cellular and Integrative Physiology and Internal Medicine, Section of Nephrology, University of Nebraska Medical Center, Omaha, Nebraska; and bpadanilam@unmc.edu.
Babu J
BJ
Padanilam
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001806:Blood Urea Nitrogen; D002453:Cell Cycle; D003404:Creatinine / Q000097:blood; D017353:Gene Deletion; D016158:Genes, p53; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009336:Necrosis / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000199:Actins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003404:Creatinine; D011065:Poly(ADP-ribose) Polymerases