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Physiol. Genomics 3: 121-131, 2000;
1094-8341/00 $5.00
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Received 21 April 2000; accepted in final form 19 June 2000.
Physiological Genomics 3:121-131 (2000)
1094-8341/00 $5.00 © 2000 American Physiological Society

Bradykinin B2 null mice are prone to renal dysplasia: gene-environment interactions in kidney development

SAMIR S. EL-DAHR1,2, LISA M. HARRISON-BERNARD2, SUSANA DIPP1, IGOR V. YOSIPIV1 and SUZANNE MELEG-SMITH3

1 Department of Pediatrics
2 Department of Physiology
3 Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana 70112

El-Dahr, Samir S., Lisa M. Harrison-Bernard, Susana Dipp, Igor V. Yosipiv, and Suzanne Meleg-Smith. Bradykinin B2 null mice are prone to renal dysplasia: gene-environment interactions in kidney development. Physiol Genomics 3: 121–131, 2000.—Congenital abnormalities of the kidney and urinary tract are a common cause of end-stage renal disease in children. Host and environment factors are implicated in the pathogenesis of aberrant renal development. However, direct evidence linking gene-environment interactions with congenital renal disease is lacking. We report an animal model of renal dysgenesis that is dependent on a defined genetic defect and specific embryonic stressor. Specifically, mice that are deficient in the bradykinin type 2 receptor gene (B2) and salt loaded during embryogenesis acquire an aberrant kidney phenotype and die shortly after birth. In contrast, B2 mutant mice maintained on normal sodium intake or salt-loaded wild-type mice do not develop kidney abnormalities. The kidney abnormality is evident histologically on embryonic day 16, shortly after the onset of metanephric B2 gene expression, and consists of distorted renal architecture, foci of tubular dysgenesis, and cyst formation. The dysplastic tubules are of distal nephron origin [Dolichos biflorus agglutinin (DBA)- and aquaporin-2 (AQP2) positive, and angiotensinogen negative]. Neonatal antihypertensive therapy fails to ameliorate the renal abnormalities, arguing against the possibility that the nephropathy is a consequence of early hypertension. Moreover, the nephropathy is intrinsic to the embryo, because B2 homozygous offspring from heterozygous parents exhibit the same renal phenotype as offspring from homozygous null parents. Further characterization of the renal phenotype revealed an important genetic background effect since the penetrance of the congenital nephropathy is increased substantially upon backcrossing of 129/BL6 B2 mutants to a uniform C57BL/6J. We conclude that the type 2 bradykinin receptor is required for the maintenance of metanephric structure and epithelial integrity in the presence of fetal stress. This study provides a "proof-of-principle" that defined gene-environment interactions are a cause of congenital renal disease.

genetic susceptibility; nephrogenesis; G protein-coupled receptors; gene targeting




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