Tubular p53 regulates multiple genes to mediate AKI.
A pathogenic role of p53 in AKI was suggested a decade ago but remains controversial. Indeed, recent work indicates that inhibition of p53 protects against ischemic AKI in rats but exacerbates AKI in mice. One intriguing possibility is that p53 has cell type-specific roles in AKI. To determine the role of tubular p53, we generated two conditional gene knockout mouse models, in which p53 is specifically ablated from proximal tubules or other tubular segments, including distal tubules, loops of Henle, and medullary collecting ducts. Proximal tubule p53 knockout (PT-p53-KO) mice were resistant to ischemic and cisplatin nephrotoxic AKI, which was indicated by the analysis of renal function, histology, apoptosis, and inflammation. However, other tubular p53 knockout (OT-p53-KO) mice were sensitive to AKI. Mechanistically, AKI associated with the upregulation of several known p53 target genes, including Bax, p53-upregulated modulator of apoptosis-α, p21, and Siva, and this association was attenuated in PT-p53-KO mice. In global expression analysis, ischemic AKI induced 371 genes in wild-type kidney cortical tissues, but the induction of 31 of these genes was abrogated in PT-p53-KO tissues. These 31 genes included regulators of cell death, metabolism, signal transduction, oxidative stress, and mitochondria. These results suggest that p53 in proximal tubular cells promotes AKI, whereas p53 in other tubular cells does not.
Departments of Emergency Medicine and Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and Department of Cellular Biology and Anatomy, Vascular Biology Center and Department of Biochemistry and Molecular Biology, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.
Dongshan
D
Zhang
Departments of Emergency Medicine and Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and Department of Cellular Biology and Anatomy, Vascular Biology Center and Department of Biochemistry and Molecular Biology, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.
Yu
Y
Liu
Department of Cellular Biology and Anatomy, Vascular Biology Center and Department of Biochemistry and Molecular Biology, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.
Qingqing
Q
Wei
Department of Cellular Biology and Anatomy, Vascular Biology Center and Department of Biochemistry and Molecular Biology, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.
Yuqing
Y
Huo
Department of Cellular Biology and Anatomy, Vascular Biology Center and Department of Biochemistry and Molecular Biology, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.
Kebin
K
Liu
Departments of Emergency Medicine and Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and.
Fuyou
F
Liu
Departments of Emergency Medicine and Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and Department of Cellular Biology and Anatomy, Vascular Biology Center and Department of Biochemistry and Molecular Biology, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia zdong@gru.edu.
Zheng
Z
Dong
D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D005260:Female; D005786:Gene Expression Regulation; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53