Tubular p53 regulates multiple genes to mediate AKI

Dongshan Zhang, Yu Liu, QingQing Wei, Yuqing Huo, Kebin Liu, Fuyou Liu, Zheng Dong

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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 inmice. 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- a, p21, and Siva, and this association was attenuated in PT-p53-KO mice. In global expression analysis, ischemic AKI induced 371 genes inwild-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.

Original languageEnglish (US)
Pages (from-to)2278-2289
Number of pages12
JournalJournal of the American Society of Nephrology
Volume25
Issue number10
DOIs
StatePublished - Oct 1 2014

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Knockout Mice
Genes
Apoptosis
Loop of Henle
Kidney
Gene Knockout Techniques
p53 Genes
Regulator Genes
Cisplatin
Signal Transduction
Histology
Mitochondria
Oxidative Stress
Cell Death
Up-Regulation
Inflammation

ASJC Scopus subject areas

  • Nephrology

Cite this

Tubular p53 regulates multiple genes to mediate AKI. / Zhang, Dongshan; Liu, Yu; Wei, QingQing; Huo, Yuqing; Liu, Kebin; Liu, Fuyou; Dong, Zheng.

In: Journal of the American Society of Nephrology, Vol. 25, No. 10, 01.10.2014, p. 2278-2289.

Research output: Contribution to journalArticle

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