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REGULATION IN GENETICALLY MODIFIED ANIMALS

Renal and blood pressure phenotype in 18-mo-old bradykinin B₂R(-/-)^CRD mice

Departments of ¹Physiology and ²Pediatrics, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112

Submitted 12 March 2003 ; accepted in final form 12 June 2003

Aberrant gene-environment interactions are implicated in the pathogenesis of congenital renal dysgenesis (CRD), a leading cause of renal failure in infants and children. We have recently developed an animal model of CRD that is caused by gestational salt stress (5% NaCl diet; HS) of bradykinin B₂R null mice [B₂R(-/-)^CRD; El-Dahr SS, Harrison-Bernard LM, Dipp S, Yosipiv IV, and Meleg-Smith S. Physiol Genomics 3: 121-131, 2000.]. Developing B₂R(-/-)^CRD mice exhibit tubular and glomerular cysts, stromal expansion, and loss of corticomedullary differentiation. In addition, B₂R(-/-)^CRD mice exhibit transient hypertension from 2 to 4 mo of age. The present study was designed to determine the long-term consequences of CRD on renal morphology and salt sensitivity of blood pressure in B₂R(-/-)^CRD mice. One-year- and 18-mo-old B₂R(-/-)^CRD mice exhibited stunted renal growth, glomerular cystic abnormalities, and collecting duct ectasia. Moreover, tumors of mesenchymal cell origin emerged in the dysplastic kidneys of 90% of 1-yr-old and 100% of 18-mo-old B₂R(-/-)^CRD mice but not in age-matched B₂R(-/-) or wild-type mice. When challenged with an HS diet, 18-mo-old B₂R(-/-)^CRD exhibited a significant rise in systolic and diastolic blood pressures and more pronounced natriuresis and diuresis compared with salt-loaded 18-mo-old wild-type mice. Kidney aquaporin-2 expression was decreased by 50%, whereas renin, ANG type 1 receptor, and Na⁺-K⁺-ATPase levels were not different in B₂R(-/-)^CRD mice compared with controls. In conclusion, this study demonstrates that B₂R(-/-)^CRD mice exhibit permanent phenotypic and functional abnormalities in renal growth and differentiation. This novel model of human disease links gene-environment interactions with renal development and blood pressure homeostasis.

kidney development; salt sensitivity; kallikrein-kinin; aquaporin

This article has been cited by other articles:

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