A novel pathological role of p53 in kidney development revealed by gene-environment interactions

American Journal of Physiology. Renal Physiology
Hao FanSamir S El-Dahr

Abstract

Gene-environment interactions are implicated in congenital human disorders. Accordingly, there is a pressing need to develop animal models of human disease, which are the product of defined gene-environment interactions. Previously, our laboratory demonstrated that gestational salt stress of bradykinin B(2) receptor (B(2)R)-null mice induces renal dysgenesis and early death of the offspring. In contrast, salt-stressed B(2)R +/+ or +/- littermates have normal development. The present study investigates the mechanisms underlying the susceptibility of B(2)R-null mice to renal dysgenesis. Proteomic and conventional Western blot screens identified E-cadherin among the differentially repressed proteins in B(2)R-/- kidneys, whereas the checkpoint kinase Chk1 and its substrate P-Ser(20) p53 were induced. We tested the hypothesis that p53 mediates repression of E-cadherin gene expression and is causally linked to the renal dysgenesis. Genetic crosses between B(2)R -/- and p53+/- mice revealed that germline reduction of p53 gene dosage rescues B(2)R-/- mice from renal dysgenesis and restores kidney E-cadherin gene expression. Furthermore, gamma-irradiation induces repression of E-cadherin gene expression in p53+/+ but not -/- cells. In t...Continue Reading

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Citations

Aug 30, 2008·American Journal of Physiology. Renal Physiology·Samir S El-DahrSusana Dipp
Jul 8, 2009·Pediatric Research·Ozlem Pinar BulutSamir El-Dahr
Sep 5, 2009·Journal of the American Society of Nephrology : JASN·Zubaida SaifudeenSamir S El-Dahr
Apr 12, 2005·American Journal of Physiology. Renal Physiology·Carlton M Bates
Sep 8, 2005·American Journal of Physiology. Renal Physiology·Rocio ZamoranoJames V Gainer
Mar 31, 2006·American Journal of Physiology. Renal Physiology·Hao FanSamir S El-Dahr
Jul 10, 2014·Physiological Genomics·Lei YanSamir S El-Dahr
Jun 23, 2012·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Shaowei Chen, Samir S El-Dahr

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