title: Inactivation of Bardet-Biedl syndrome genes causes kidney defects.
abstract: Bardet-Biedl syndrome (BBS) is a rare hereditary autosomal recessive disease associated with several features including obesity, hypertension, and renal abnormalities. The underlying mechanisms of renal defects associated with BBS remain poorly defined. We examined the histological, molecular, and functional renal changes in BBS mouse models that have features of the human disorder. Interestingly, obese hypertensive Bbs4(-/-) mice exhibited inflammatory infiltration and renal cysts, whereas the obese normotensive Bbs2(-/-) mice had only minor inflammatory infiltration. Accordingly, the expression level of inducible nitric oxide synthase was elevated in the kidney of both BBS mice with a more marked increase in Bbs4(-/-) mice. In contrast, endothelial nitric oxide synthase expression was decreased in Bbs4(-/-), but not Bbs2(-/-), mice. Similarly, the expression levels of transient receptor potential vanilloid 1 and 4 channels as well as β- and γ-subunits of epithelial Na channel were significantly reduced only in the kidney of Bbs4(-/-) mice. Metabolic studies revealed changes in urine output and urinary concentrations of creatinine, blood urea nitrogen, sodium, and potassium with a more pronounced effect in Bbs4(-/-) mice. Finally, we found that calorie restriction which prevented obesity in BBS mice reversed the morphological and molecular changes found in Bbs2(-/-) and Bbs4(-/-) mice, indicating the kidney abnormalities associated with BBS are obesity related. These findings extend our understanding of the function of BBS proteins and emphasize the importance of these proteins in renal physiology.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Deng-Fu
authors.initials: DF
authors.lastname: Guo
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Beyer
authors.forename: Baoli
authors.initials: B
authors.lastname: Yang
authors.forename: Darryl Y
authors.initials: DY
authors.lastname: Nishimura
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
mesh_terms: D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D001806:Blood Urea Nitrogen; D031204:Caloric Restriction; D003404:Creatinine / Q000652:urine; D053503:Epithelial Sodium Channels / Q000032:analysis; D005260:Female; D006973:Hypertension / Q000235:genetics; D007668:Kidney / Q000002:abnormalities*; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D009765:Obesity / Q000235:genetics; D009846:Oliguria / Q000503:physiopathology; D011188:Potassium / Q000652:urine; D011506:Proteins / Q000235:genetics*; D012964:Sodium / Q000652:urine; D050916:TRPV Cation Channels / Q000032:analysis
chemical_list: C506281:BBS4 protein, mouse; C528012:Bbs2 protein, mouse; D053503:Epithelial Sodium Channels; D008869:Microtubule-Associated Proteins; D011506:Proteins; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C486576:Trpv4 protein, mouse; D012964:Sodium; D003404:Creatinine; D052250:Nitric Oxide Synthase Type III; D011188:Potassium