Senescence-associated phenotypes in Akita diabetic mice are enhanced by absence of bradykinin B2 receptors

Abstract

We have previously reported that genetically increased angiotensin-converting enzyme levels, or absence of the bradykinin B2 receptor, increase kidney damage in diabetic mice. We demonstrate here that this is part of a more general phenomenon -diabetes and, to a lesser degree, absence of the B2 receptor, independently but also largely additively when combined, enhance senescence-associated phenotypes in multiple tissues. Thus, at 12 months of age, indicators of senescence (alopecia, skin atrophy, kyphosis, osteoporosis, testicular atrophy, lipofuscin accumulation in renal proximal tubule and testicular Leydig cells, and apoptosis in the testis and intestine) are virtually absent in WT mice, detectable in B2 receptor-null mice, clearly apparent in mice diabetic because of a dominant mutation (Akita) in the Ins2 gene, and most obvious in Akita diabetic plus B2 receptor-null mice. Renal expression of several genes that encode proteins associated with senescence and/or apoptosis (TGF-β1, connective tissue growth factor, p53, α-synuclein, and forkhead box O1) increases in the same progression. Concomitant increases occur in 8-hydroxy-2′-deoxyguanosine, point mutations and deletions in kidney mitochondrial DNA, and thiobarbituric acid-reactive substances in plasma, together with decreases in the reduced form of glutathione in erythrocytes. Thus, absence of the bradykinin B2 receptor increases the oxidative stress, mitochondrial DNA damage, and many senescence-associated phenotypes already present in untreated Akita diabetic mice.

Additive renoprotective effects of B2-kinin receptor blocker and PPAR-γ agonist in uninephrectomized db/db mice

“…9 Fibronectin secretion induced by macrophage-conditioned medium was reduced by perindoprilat or BK treatment. 10 In vivo, Akita diabetic mice with absent B2R had more severe albuminuria and glomerulosclerosis, 11 and senescence-associated phenotypes 12 attenuated the anti-proteinuric effect of ramipril. 13 More recently, Bodin et al 14 showed that KLK-knock out STZ-induced mice had more severe albuminuria than WT.…”

Bradykinin potentiates cytokine‐induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression

“…The latter effect of kinins is also associated with their synergistic potentiation of IL-1-induced prostaglandin E 2 (PGE 2 ) and PGI 2 production (10,11). In addition to playing an important role in inflammationinduced bone remodeling, kinins are involved in senescence-associated bone loss, since mice double mutant for Ins2 Akita/ϩ and Bdkrb2 Ϫ/Ϫ genes exhibit a complex phenotype, including kyphosis and osteoporosis (12).…”

Bradykinine et néphroprotection

“…Nous avons montré, chez le rat diabétique, que l'expression des récepteurs glomérulaires de certaines cytokines (IGF-1, insulin-like growth factor -1, TGF-β, transforming growth factor) est augmentée lors du blocage du RB2 [28]. Ces travaux sont par ailleurs en accord avec une observation récente indiquant que la surexpression du récepteur du TGF-β est augmentée chez les souris n'exprimant plus le RB2 [29].…”

“…Une réduction de la formation de radical superoxyde et des concentrations sériques en triglycérides et cholestérol a été démon-trée après transfert du gène de la kallicréine [32][33][34]. Inversement, une aggravation du profil du stress oxydant a été décrite chez les souris n'exprimant pas le RB2 [29]. Enfin, chez le rat diabétique, notre groupe a décrit une augmentation de l'accumulation de protéines complexées à des dérivés 4-HNE (index de la peroxidation lipidique) lors du blocage du RB2 [28].…”

“…Bien que l'idée qu'une stimulation du RB2 de la BK puisse induire des effets thérapeutiques bénéfiques reste encore novatrice, ce concept émerge finalements des travaux de plusieurs groupes indépendants [28,29,[32][33][34]. Plusieurs agonistes non peptidiques sont disponibles et ont été testés dans des modèles différents [38][39][40].…”