Amelioration of progressive renal injury by genetic manipulation of Klotho gene

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 7; pp. 2331 - 2336
• Main Authors: Haruna, Yoshisuke, Kashihara, Naoki, Satoh, Minoru, Tomita, Naruya, Namikoshi, Tamehachi, Sasaki, Tamaki, Fujimori, Toshihiko, Xie, Ping, Kanwar, Yashpal S
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.02.2007; National Acad Sciences
• Subjects: Animals; Apoptosis; Biological Sciences; Disease Progression; DNA damage; Gene Expression Regulation; Genes; Genetic Therapy; Genetics; Glucuronidase - analysis; Glucuronidase - genetics; Kidney diseases; Kidney Diseases - genetics; Kidney Diseases - prevention & control; Kidney Diseases - therapy; Kidneys; Mice; Mice, Inbred Strains; Mitochondria - metabolism; Mitochondrial DNA; Nephrology; Nephrons - chemistry; Oxidases; Oxidative Stress; Physical trauma; Superoxides; Survival Rate; Tissue Distribution; Transgenes; Transgenes - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0611079104

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 [almost equal to]30% in ICGN mice, and [almost equal to]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 renoprotective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.