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.diabetes mellitus complications | kinins T he angiotensin-I converting enzyme (ACE) is a dipeptidyl carboxypeptidase, named because it removes two amino acids from the carboxyl terminus of the inactive peptide angiotensin I and converts it into the active blood pressure-raising peptide, angiotensin II. However, ACE is also a kininase and converts the active vasodilatory kinins into inactive metabolites by removing two amino acids from their carboxyl termini (1). Prior experimental findings (2) and computer simulations (3) show that modest changes in ACE levels affect the levels of its substrates much more than its products, indicating that relatively small changes in the levels of ACE affect kinin levels more than angiotensin II levels.The common insertion/deletion (I/D) polymorphism of the ACE gene in humans is due to the presence or absence of an Alu retrotransposon in the 16th intron of the gene. The polymorphism is associated with up to a twofold difference in relative plasma ACE levels (4), but the polymorphism does not significantly affect blood pressure or angiotensin II or aldosterone levels (5). Nevertheless, the I and D human ACE alleles are associated with different risks for developing diabetic complications including nephropathy (6

IL‐4 and IL‐13 inhibit IL‐1β and TNF‐α induced kinin B1 and B2 receptors through a STAT6‐dependent mechanism

“…Interestingly, kinins not only stimulate bone resorption, but also synergistically potentiate the bone resorptive effect of IL-1 (Lerner, 1991;Lerner and Modeer, 1991), by a mechanism dependent on prostaglandin production (Lerner et al, 1989). In contrast to these observations, it has been reported that mice lacking both subtypes of kinin receptors have decreased bone mass as assessed by dual emission x-ray absorptiometry (Kakoki et al, 2010). Since histomorphometric analysis was not performed, it is not possible to know if the decreased bone mass was a consequence of increased resorption or decreased formation of bone.…”

Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms

“…In diabetic Akita mice with mutation in the insulin2 gene, the lack of bradykinin receptor1 (B1R) and receptor2 (B2R) (i.e. B1R/B2R double knockout) induces profound diabetic complications, including massive albuminuria, glomerulo sclerosis, reduction of nerve conduction velocity, and marked bone mineral loss [59] . It is thus possible that B1R/ B2R and their related kinin signaling participate in the DMinduced bone loss.…”

Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man

“…Male mice, deficient in both B1 and B2 receptor, studied at 12 months of age, display mild hyperinsulinemia with normal glucose levels, indicating mild insulin resistance (Kakoki et al 2010). In ob/ob mice made deficient in both kinin receptors, mild hyperglycemia; enhanced insulin release; and hepatic abnormalities have been reported (Barros et al 2012b).…”

“…TK gene therapy has been reported to reverse insulin resistance and attenuate nephropathy in diabetic rats (Yuan et al 2007). Moreover, lack of kininogen or kinin B2 receptor impaired insulin sensitivity and glucose tolerance in nondiabetic animals, indicating that the KKS is involved in insulin action and glucose homeostasis (Damas et al 1999, Duka et al 2001, Kakoki et al 2010.…”