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

Department of Pediatrics, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, Louisiana

Submitted 1 July 2004 ; accepted in final form 14 September 2004

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 B₂ receptor (B₂R)-null mice induces renal dysgenesis and early death of the offspring (El-Dahr SS, Harrison-Bernard LM, Dipp S, Yosipiv IV, and Meleg-Smith S. Physiol Genomics 3: 121–131, 2000). In contrast, salt-stressed B₂R +/+ or +/– littermates have normal development. The present study investigates the mechanisms underlying the susceptibility of B₂R-null mice to renal dysgenesis. Proteomic and conventional Western blot screens identified E-cadherin among the differentially repressed proteins in B₂R–/– kidneys, whereas the checkpoint kinase Chk1 and its substrate P-Ser²⁰ 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 B₂R –/– and p53+/– mice revealed that germline reduction of p53 gene dosage rescues B₂R–/– mice from renal dysgenesis and restores kidney E-cadherin gene expression. Furthermore, -irradiation induces repression of E-cadherin gene expression in p53+/+ but not –/– cells. In transient transfection assays, p53 repressed human E-cadherin promoter-driven reporter activity, whereas a mutant p53, which cannot bind DNA, did not. Functional promoter analysis indicated the presence of a p53-responsive element in exon 1, which partially mediates p53-induced repression. Chromatin immunoprecipitation assays revealed that p53 inhibits histone acetylation of the E-cadherin promoter. Treatment with a histone deacetylase inhibitor reversed both p53-mediated promoter repression and deacetylation. In conclusion, this study demonstrates that gene-environment interactions cooperate to induce congenital defects through p53 activation.

bradykinin B₂ receptor; knockout mice; checkpoint kinase; histone acetylation

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