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J Am Soc Nephrol. 2016 Jan;27(1):144-57. doi: 10.1681/ASN.2014111109. Epub 2015 May 12.

Podocyte p53 Limits the Severity of Experimental Alport Syndrome.

Author information

1
Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan;
2
Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan; and.
3
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
4
Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; hirokai@gpo.kumamoto-u.ac.jp.

Abstract

Alport syndrome (AS) is one of the most common types of inherited nephritis caused by mutation in one of the glomerular basement membrane components. AS is characterized by proteinuria at early stage of the disease and glomerular hyperplastic phenotype and renal fibrosis at late stage. Here, we show that global deficiency of tumor suppressor p53 significantly accelerated AS progression in X-linked AS mice and decreased the lifespan of these mice. p53 protein expression was detected in 21-week-old wild-type mice but not in age-matched AS mice. Expression of proinflammatory cytokines and profibrotic genes was higher in p53(+/-) AS mice than in p53(+/+) AS mice. In vitro experiments revealed that p53 modulates podocyte migration and positively regulates the expression of podocyte-specific genes. We established podocyte-specific p53 (pod-p53)-deficient AS mice, and determined that pod-p53 deficiency enhanced the AS-induced renal dysfunction, foot process effacement, and alteration of gene-expression pattern in glomeruli. These results reveal a protective role of p53 in the progression of AS and in maintaining glomerular homeostasis by modulating the hyperplastic phenotype of podocytes in AS.

KEYWORDS:

Alport-s syndrome; mouse; p53; p53 knockout; podocyte; renal progression

PMID:
25967122
PMCID:
PMC4696573
DOI:
10.1681/ASN.2014111109
[Indexed for MEDLINE]
Free PMC Article

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