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1 Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA, USA
2 Department of Pediatrics, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, LA, USA
* To whom correspondence should be addressed. E-mail: seldahr{at}tulane.edu.
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; Physiol. Genomics, 2000). Developing B2R-/-CRD mice exhibit tubular and glomerular cysts, stromal expansion and loss of cortico-medullary differentiation. In addition, B2R-/-CRD mice exhibit transient hypertension from 2-4 months 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 month 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 one-year old and 100% of 18-month-old B2R-/-CRD but not in age-matched B2R-/- or wild-type mice. When challenged with a HS diet, 18-month-old B2R-/-CRD exhibited a significant rise in systolic and diastolic blood pressures and more pronounced natriuresis and diuresis as compared to salt-loaded 18-month-old wild-type mice. Kidney aquaporin-2 expression was decreased by 50%, whereas renin, AT1 receptor, and Na+-K+-ATPase levels were not different in B2R-/-CRD as compared to 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.
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