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

Abstract

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.