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This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/F670    most recent 00037.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fan, H. Articles by El-Dahr, S. S. Search for Related Content PubMed PubMed Citation Articles by Fan, H. Articles by El-Dahr, S. S.

Susceptibility to metanephric apoptosis in bradykinin B2 receptor null mice via the p53-Bax pathway

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

Submitted 1 February 2006 ; accepted in final form 8 March 2006

In response to gestational high salt intake, BdkrB2–/– embryos acquire an aberrant renal phenotype mimicking renal dysplasia in humans. Genetic analysis identified p53 as a mediator of the renal dysplasia in salt-stressed BdkrB2–/– mice, acting partly via repression of terminal epithelial differentiation genes. The present study tested the hypothesis that inactivation of BdkrB2 predisposes the salt-stressed embryo to p53-mediated metanephric apoptosis. Newborn BdkrB2–/– pups exhibited hyperphosphorylation of metanephric p53 on serine 20 (mouse serine 23), a modification known to increase p53 stability and apoptotic activity. As a result, there was widespread, ectopic expression of p53 in the BdkrB2–/– kidney. However, no differences were found in the apoptosis index or gene expression in BdkrB2–/– and +/+ kidneys, indicating that p53 stabilization as a result of BdkrB2 inactivation is not sufficient to induce metanephric apoptosis. On gestational salt stress, fulminant metanephric apoptosis and enhanced Bax gene expression occurred in BdkrB2–/– but not their +/– or +/+ littermates. Germline deletion of p53 from BdkrB2–/– mice prevented Bax activation and normalized the apoptosis index. Rescue of metanephric apoptosis in BdkrB2–/– mice was similarly achieved by Bax gene deletion. Aberrant apoptosis in salt-stressed BdkrB2–/– mice was triggered on embryonic day E15.5 and involved both ureteric bud (UB) and metanephric mesenchyme-derived nephron elements. Cultured E12.5 salt-stressed BdkrB2–/– metanephroi manifested stunted UB branching compared with +/– and +/+ littermates; the abnormal UB branching was corrected by p53 deletion. Our results suggest a model whereby a seemingly silent genetic mutation of BdkrB2 predisposes mice to renal dysplasia by creating a "preapoptotic" state through p53 activation.

kidney development; ureteric bud branching; kallikrein-kinin system