title: Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice.
abstract: An insertion polymorphism of the angiotensin-I converting enzyme gene (ACE) is common in humans and the higher expressing allele is associated with an increased risk of diabetic complications. The ACE polymorphism does not significantly affect blood pressure or angiotensin II levels, suggesting that the kallikrein-kinin system partly mediates the effects of the polymorphism. We have therefore explored the influence of lack of both bradykinin receptors (B1R and B2R) on diabetic nephropathy, neuropathy, and osteopathy in male mice heterozygous for the Akita diabetogenic mutation in the insulin 2 gene (Ins2). We find that all of the detrimental phenotypes observed in Akita diabetes are enhanced by lack of both B1R and B2R, including urinary albumin excretion, glomerulosclerosis, glomerular basement membrane thickening, mitochondrial DNA deletions, reduction of nerve conduction velocities and of heat sensation, and bone mineral loss. Absence of the bradykinin receptors also enhances the diabetes-associated increases in plasma thiobarbituric acid-reactive substances, mitochondrial DNA deletions, and renal expression of fibrogenic genes, including transforming growth factor beta1, connective tissue growth factor, and endothelin-1. Thus, lack of B1R and B2R exacerbates diabetic complications. The enhanced renal injury in diabetic mice caused by lack of B1R and B2R may be mediated by a combination of increases in oxidative stress, mitochondrial DNA damage and over expression of fibrogenic genes.
authors.affiliation: Department of Pathology and Laboratory Medicine and Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA. mkakoki@med.unc.edu
authors.forename: Masao
authors.initials: M
authors.lastname: Kakoki
authors.forename: Kelli A
authors.initials: KA
authors.lastname: Sullivan
authors.forename: Carey
authors.initials: C
authors.lastname: Backus
authors.forename: John M
authors.initials: JM
authors.lastname: Hayes
authors.forename: Sang Su
authors.initials: SS
authors.lastname: Oh
authors.forename: Kunjie
authors.initials: K
authors.lastname: Hua
authors.forename: Adil M H
authors.initials: AM
authors.lastname: Gasim
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomita
authors.forename: Ruriko
authors.initials: R
authors.lastname: Grant
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Nossov
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: J Charles
authors.initials: JC
authors.lastname: Jennette
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
authors.forename: Oliver
authors.initials: O
authors.lastname: Smithies
mesh_terms: D000818:Animals; D015519:Bone Density; D004272:DNA, Mitochondrial / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003929:Diabetic Neuropathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010024:Osteoporosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D043783:Receptor, Bradykinin B1 / Q000172:deficiency* / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000172:deficiency* / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2