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Senescence-associated phenotypes in Akita diabetic mice are enhanced by absence of bradykinin B2 receptors
Masao Kakoki, … , J. Charles Jennette, Oliver Smithies
Masao Kakoki, … , J. Charles Jennette, Oliver Smithies
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1302-1309. https://doi.org/10.1172/JCI26958.
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Research Article Aging

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

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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.

Authors

Masao Kakoki, Catherine M. Kizer, Xianwen Yi, Nobuyuki Takahashi, Hyung-Suk Kim, C. Robert Bagnell, Cora-Jean S. Edgell, Nobuyo Maeda, J. Charles Jennette, Oliver Smithies

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Figure 1

Appearance and associated indicators of senescence in mice at age 12 months.

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Appearance and associated indicators of senescence in mice at age 12 mon...
(A) General appearance of male mice with the following genotypes: WT at both the insulin 2 and the bradykinin B2 receptor loci, homozygous null for the B2 receptor (Bdkrb2–/–), heterozygous Akita for insulin 2 (Ins2Akita/+), and doubly mutant (Bdkrb2–/–Ins2Akita/+). Kyphosis was moderate in the Akita diabetic mouse; it was severe in the doubly mutant animal, which also exhibited marked alopecia. The animals imaged were among the most severely affected of each genotype. (B) H&E-stained abdominal skin of mice with the same 4 genotypes. Scale bars: 1 mm. Subcutaneous fat (asterisks) was present in both nondiabetic animals but was absent in the diabetic animals. The skin of the double mutant was thin and had few hair follicles. The areas selected for imaging are representative of each genotype. (C) Bone mineral density of femurs of mice of the 4 genotypes, assessed with dual-emission x-ray absorptiometry. Data are presented as means ± SEM with the numbers of animals shown in white digits (see Supplemental Table 4 for 2-factor ANOVA analysis).
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