Bradykinin B-2 null mice are prone to renal dysplasia: gene-environment interactions in kidney development

Congenital abnormalities of the kidney and urinary tract are a common cause of end-stage renal disease in children. Host and environment factors are i mplicated in the pathogenesis of aberrant renal development. However, direc t evidence linking gene-environment interactions with congenital renal dise ase is lacking. We report an animal model of renal dysgenesis that is depen dent on a defined genetic defect and specific embryonic stressor. Specifica lly, mice that are deficient in the bradykinin type 2 receptor gene (B-2) a nd salt loaded during embryogenesis acquire an aberrant kidney phenotype an d die shortly after birth. In contrast, B-2 mutant mice maintained on norma l sodium intake or salt-loaded wild-type mice do not develop kidney abnorma lities. The kidney abnormality is evident histologically on embryonic day 1 6, shortly after the onset of metanephric B-2 gene expression, and consists of distorted renal architecture, foci of tubular dysgenesis, and cyst form ation. The dysplastic tubules are of distal nephron origin [Dolichos biflor us agglutinin (DBA)- and aquaporin-2 (AQP2) positive, and angiotensinogen n egative]. Neonatal antihypertensive therapy fails to ameliorate the renal a bnormalities, arguing against the possibility that the nephropathy is a con sequence of early hypertension. Moreover, the nephropathy is intrinsic to t he embryo, because B-2 homozygous offspring from heterozygous parents exhib it the same renal phenotype as offspring from homozygous null parents. Furt her characterization of the renal phenotype revealed an important genetic b ackground effect since the penetrance of the congenital nephropathy is incr eased substantially upon backcrossing of 129/ BL6 B-2 mutants to a uniform C57BL/6J. We conclude that the type 2 bradykinin receptor is required for t he maintenance of metanephric structure and epithelial integrity in the pre sence of fetal stress. This study provides a "proof-of-principle" that defi ned gene-environment interactions are a cause of congenital renal disease.