| Authors |
Kakoki M, Kizer CM, Yi X, Takahashi N, Kim H-S, Bagnell CR, Edgell CJS, Maeda N,
Jennette JC, Smithies O
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| Submitted By |
Oliver Smithies on 2/10/2009 |
| Status |
Published |
| Journal |
The Journal of clinical investigation |
| Year |
2006 |
| Date Published |
5/1/2006 |
| Volume : Pages |
116 : 1302 - 1309 |
| PubMed Reference |
16604193 |
| 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-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.
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