Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice.
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.
Kakoki
Masao
M
Department of Pathology and Laboratory Medicine and Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA. mkakoki@med.unc.edu
Sullivan
Kelli A
KA
Backus
Carey
C
Hayes
John M
JM
Oh
Sang Su
SS
Hua
Kunjie
K
Gasim
Adil M H
AM
Tomita
Hirofumi
H
Grant
Ruriko
R
Nossov
Sarah B
SB
Kim
Hyung-Suk
HS
Jennette
J Charles
JC
Feldman
Eva L
EL
Smithies
Oliver
O
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
D004272:DNA, Mitochondrial; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2