Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 7, Pages 2331-2336Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0611079104
Keywords
aging; glomerulonephritis; oxidative stress; tubular interstitial diseaset
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Funding
- NIDDK NIH HHS [R01 DK060635, R37 DK028492, DK28492, DK60635, R01 DK028492] Funding Source: Medline
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Klotho, an antiaging gene with restricted organ distribution, is mainly expressed in the kidney tubules; the mutant mice have shortened life span, arteriosclerosis, anemia, and osteoporesis, features common to patients with chronic renal failure. Conceivably, the reduction of the Klotho gene expression may contribute to the development of kidney failure; alternatively, its overexpression may lead to the amelioration of renal injury in an ICR-derived glomerulonephritis (ICGN) mouse model with subtle immune complex-mediated disease. To address this issue, four different strains of mice were generated by cross-breeding: ICGN mice without the Klotho transgene (ICGN), ICGN mice with the Klotho transgene (ICGN/kITG), wild-type mice with the Klotho transgene (kITG), and wild-type mice without the Klotho transgene (control). At 40 weeks old, the survival rate was approximate to 30% in ICGN mice, and approximate to 70% in the ICGN/kITG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome c oxidase activity but a reduction in beta-galactosidase activity (a senescence-associated protein), mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax protein expression and apoptosis. Interestingly, improvement was seen in both the tubular and glomerular compartments of the kidney, although Klotho is exclusively confined to the tubules, suggesting that its gene product has a remarkable renoprotective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.
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