title: Renal and blood pressure phenotype in 18-mo-old bradykinin B2R(-/-)CRD mice.
abstract: 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.
authors.affiliation: Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112-2699, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Harrison-Bernard
authors.forename: Susana
authors.initials: S
authors.lastname: Dipp
authors.forename: Samir S
authors.initials: SS
authors.lastname: El-Dahr
mesh_terms: D000758:Anesthesia; D000818:Animals; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D004231:Diuresis / Q000502:physiology; D005260:Female; D007668:Kidney / Q000002:abnormalities* / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009318:Natriuresis / Q000502:physiology; D010641:Phenotype; D011188:Potassium / Q000652:urine; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin / Q000378:metabolism; D018002:Receptors, Bradykinin / Q000235:genetics*; D012083:Renin / Q000378:metabolism; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D011945:Receptors, Angiotensin; D018002:Receptors, Bradykinin; D017673:Sodium Chloride, Dietary; D012964:Sodium; D012083:Renin; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium