Senescence-associated phenotypes in Akita diabetic mice are enhanced by absence of bradykinin B2 receptors.
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-beta1, connective tissue growth factor, p53, alpha-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.
Kakoki
Masao
M
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7525, USA.
Kizer
Catherine M
CM
Yi
Xianwen
X
Takahashi
Nobuyuki
N
Kim
Hyung-Suk
HS
Bagnell
C Robert
CR
Edgell
Cora-Jean S
CJ
Maeda
Nobuyo
N
Jennette
J Charles
JC
Smithies
Oliver
O
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence; D004272:DNA, Mitochondrial / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003920:Diabetes Mellitus / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D043782:Receptor, Bradykinin B2 / Q000235:genetics* / Q000502:physiology*
D004272:DNA, Mitochondrial; D043782:Receptor, Bradykinin B2; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine