TY - JOUR
T1 - Amelioration of progressive renal injury by genetic manipulation of Klotho gene
AU - Haruna, Yoshisuke
AU - Kashihara, Naoki
AU - Satoh, Minoru
AU - Tomita, Naruya
AU - Namikoshi, Tamehachi
AU - Sasaki, Tamaki
AU - Fujimori, Toshihiko
AU - Xie, Ping
AU - Kanwar, Yashpal S.
PY - 2007/2/13
Y1 - 2007/2/13
N2 - 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/klTG), wild-type mice with the Klotho transgene (klTG), and wild-type mice without the Klotho transgene (control). At 40 weeks old, the survival rate was ≈30% in ICGN mice, and ≈70% in the ICGN/klTG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome c oxidase activity but a reduction in β-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 reno-protective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.
AB - 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/klTG), wild-type mice with the Klotho transgene (klTG), and wild-type mice without the Klotho transgene (control). At 40 weeks old, the survival rate was ≈30% in ICGN mice, and ≈70% in the ICGN/klTG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome c oxidase activity but a reduction in β-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 reno-protective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.
KW - Aging
KW - Glomerulonephritis
KW - Oxidative stress
KW - Tubular interstitial disease
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U2 - 10.1073/pnas.0611079104
DO - 10.1073/pnas.0611079104
M3 - Article
C2 - 17287345
AN - SCOPUS:33847781131
SN - 0027-8424
VL - 104
SP - 2331
EP - 2336
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -