title: Amelioration of progressive renal injury by genetic manipulation of Klotho gene.
abstract: 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 approximately 30% in ICGN mice, and approximately 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 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.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan.
authors.forename: Yoshisuke
authors.initials: Y
authors.lastname: Haruna
authors.forename: Naoki
authors.initials: N
authors.lastname: Kashihara
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Naruya
authors.initials: N
authors.lastname: Tomita
authors.forename: Tamehachi
authors.initials: T
authors.lastname: Namikoshi
authors.forename: Tamaki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujimori
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
mesh_terms: D000818:Animals; D018450:Disease Progression; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005966:Glucuronidase / Q000032:analysis / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics* / Q000517:prevention & control / Q000628:therapy*; D000090265:Klotho Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism; D009399:Nephrons / Q000737:chemistry; D018384:Oxidative Stress; D015996:Survival Rate; D014018:Tissue Distribution; D019076:Transgenes / Q000502:physiology
chemical_list: D005966:Glucuronidase; D000090265:Klotho Proteins