Amelioration of progressive renal injury by genetic manipulation of Klotho gene

Yoshisuke Haruna, Naoki Kashihara*, Minoru Satoh, Naruya Tomita, Tamehachi Namikoshi, Tamaki Sasaki, Toshihiko Fujimori, Ping Xie, Yashpal S. Kanwar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

193 Scopus citations

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 ≈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.

Original languageEnglish (US)
Pages (from-to)2331-2336
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number7
DOIs
StatePublished - Feb 13 2007

Keywords

  • Aging
  • Glomerulonephritis
  • Oxidative stress
  • Tubular interstitial disease

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Amelioration of progressive renal injury by genetic manipulation of Klotho gene'. Together they form a unique fingerprint.

Cite this