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Abstract: TH-OR017

Klotho Overexpression Improves Interstitial Fibrosis, Accumulation of Cell Cycle Arrested Cells, and Increased Levels of Oxidative Stress in the Kidneys of Aging Mice

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Ohishi, Hiroaki, Hiroshima University Hospital, Hiroshima, Japan
  • Doi, Shigehiro, Hiroshima University Hospital, Hiroshima, Japan
  • Nakashima, Ayumu, Hiroshima University Hospital, Hiroshima, Japan
  • Masaki, Takao, Hiroshima University Hospital, Hiroshima, Japan

Group or Team Name

  • Department of Nephrology
Background

Klotho is reported to suppress growth factor signaling by transforming growth factor (TGF)-β1, insulin-like growth factor (IGF)-1, and Wnt. Notably, previous studies have reported that renal function decreases with age, and that interstitial fibrosis, accumulation of cell cycle arrested cells, and increased levels of oxidative stress are major features of the aging kidney. In this study, we investigated whether klotho overexpression improves these factors in the kidneys of aging mice together with the expression of growth factor signaling molecules.

Methods

Male mice that overexpress klotho under the control of the human elongation factor 1 promoter EFmKL46 (KLTG) or wild type 129 mice (WT) were used. Mice at 2 and 24 months old were defined as young mice and aging mice, respectively. Expression of klotho, fibrotic markers (α-smooth muscle actin, vimentin, collagen I, collagen III), cell cycle markers (p16, p21, p53, proliferating cell nuclear antigen), and oxidative stress markers (8-hydroxy-2′-deoxyguanosine, manganese superoxide dismutase, catalase, 3-nitroturosine) were examined using immunohistochemistry, western blotting, and/or quantitative PCR. We also investigated the expression of TGF-β1 (Smad2/3/4), IGF-1 (c-Jun N-terminal kinase, extracellular signal-regulated kinase, p38, protein kinase B, forkhead box protein O1), and Wnt (β-catenin, RAS-related C3 botulinus toxin substrate 1) signaling molecules.

Results

Klotho expression decreased in aging WT mice, whereas it was maintained in aging KLTG mice. Although expression of fibrotic markers did not differ between young KLTG and WT mice, they were significantly suppressed in aging KLTG mice compared with aging WT mice. Similarly, aging KLTG mice demonstrated significantly less expression of cell cycle arrest markers, as well as oxidative stress markers, than aging WT mice. Furthermore, expression of TGF-β1, IGF-1, and Wnt signaling molecules increased in aging WT mice; however, this upregulation was not observed in aging KLTG mice.

Conclusion

Klotho overexpression protects against kidney aging that is characterized by interstitial fibrosis, accumulation of cell cycle arrested cells, and increased levels of oxidative stress in mice, which is accompanied by suppression of signaling for multiple growth factors.

Funding

  • Commercial Support