Bradykinin B2 receptor null mice harboring a Ser 23-to-Ala substitution in the p53 gene are protected from renal dysgenesis

Samir S. El-Dahr, Karam Aboudehen, Susana Dipp

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

A physiological cross talk operates between the tumor suppressor protein p53 and the bradykinin B2 receptor (BdkrB2) during renal organogenesis. Thus, although BdkrB2 is a target for p53-mediated transcriptional activation, BdkrB2 is required to restrict p53 proapoptotic activity. We previously demonstrated that BdkrB2-/- embryos exposed to gestational salt stress develop renal dysgenesis as a result of p53-mediated apoptosis of nephron progenitors and repression of the terminal differentiation program. Compared with wild-type kidneys, BdkrB2-/- express abnormally high levels of the Checkpoint kinase (Chk1), which activates p53 via Ser23 phosphorylation. To define the functional relevance of p53 S23 phosphorylation, we generated a compound strain of BdkrB2 -/- mice harboring a homozygous Ser23-to-Ala (S23A) mutation in the p53 gene by crossing BdkrB2-/- with p53 S23A knockin mice. Unlike salt-stressed BdkrB2-/- pups, which exhibit renal dysgenesis, homozygous S23A;BdkrB2-/- littermates are protected and have normal renal development. Heterozygous S23A;BdkrB2 -/- mice have an intermediate phenotype. The p53-S23A substitution was associated with amelioration of apoptosis and restored markers of nephrogenesis and tubulogenesis. Real-time quantitative RT-PCR of terminal differentiation genes demonstrated that the S23A substitution restored normal expression patterns of aquaporin-2, Na-Cl cotransporter, Na-K-2Cl cotransporter, Na-bicarbonate cotransporter, and Sglt1. We conclude that p53 phosphorylation on Ser23 is an essential step in the signaling pathway mediating the susceptibility of BdkrB2-/- mutants to renal dysgenesis.

Original languageEnglish (US)
Pages (from-to)F1404-F1413
JournalAmerican Journal of Physiology - Renal Physiology
Volume295
Issue number5
DOIs
StatePublished - Nov 2008

Keywords

  • Gene knockin
  • Gene knockout
  • Kidney development
  • Nephrogenesis

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