Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy,
and bone mineral loss in Akita diabetic mice.
Authors Kakoki M, Sullivan KA, Backus C, Hayes JM, Oh SS, Hua K, Gasim AM, Tomita H,
Grant R, Nossov SB, Kim HS, Jennette JC, Feldman EL, Smithies O
Submitted By Oliver Smithies on 6/23/2010
Status Published
Journal Proceedings of the National Academy of Sciences of the United States of America
Year 2010
Date Published 6/1/2010
Volume : Pages 107 : 10190 - 10195
PubMed Reference 20479236
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.

Investigators with authorship
Eva FeldmanUniversity of Michigan
Oliver SmithiesUniversity of North Carolina


Aceangiotensin converting enzyme
Bdkrb2bradykinin receptor, beta 2
Edn1endothelin 1
Ins2insulin II
Tgfb1transforming growth factor, beta 1
Tgfbr1transforming growth factor, beta receptor I
Bdkrb1bradykinin receptor, beta 1