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Abstract: TH-PO614

Inhibiting Na/K-ATPase Oxidant Amplification Loop Regulates Aging in C57B16 Old Mice

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1301 Health Maintenance, Nutrition, and Metabolism: Basic

Authors

  • Klug, Rebecca Lynn, Marshall University, Joan C. Edwards School of Medicine , Huntington, West Virginia, United States
  • Pratt, Rebecca, Marshall University School of Medicine, Huntington, West Virginia, United States
  • Liu, Jiang, Marshall University, Joan C. Edwards School of Medicine , Huntington, West Virginia, United States
  • Xie, Zi-jian, Marshall University, Huntington, West Virginia, United States
  • Sodhi, Komal, Marshall University, Joan C. Edwards School of Medicine , Huntington, West Virginia, United States
  • Shapiro, Joseph I., Marshall University School of Medicine, Huntington, West Virginia, United States
Background

Aging is driven by accumulation of oxidative damage; Na/K-ATPase signaling amplifies oxidants and is linked to several oxidation-related diseases. The progressive decline of physiological integrity, manifests as: loss of cell division, oxidative stress, DNA damage and overexpression of senescence genes. Oxidant stress causes cellular and DNA damage contributing to impaired physiological function, disease development, and life span reduction. As we identified, the Na/K-ATPase amplifies oxidant signaling and we speculate that a peptide inhibiting this pathway, pNaKtide, may be effective to regulate cellular senescence, thus delaying and/or reversing aging by attenuating oxidative stress.

Methods

Using human fibroblasts we evaluated levels of senescence markers, cell injury, apoptosis, and Na/K-ATPase signaling activation, with and without pNaKtide. C57Bl6 male mice, young (4 months) and old (17 months) were fed normal chow diet or Western Diet (WD). They were randomly divided into 6 groups: (1) Young Control, (2) Young+pNaKtide (3) Old+Control, (4) Old+pNaKtide (5) Old+WD, (6) Old+WD+pNaKtide. After 8 weeks of control or WD diet, groups 2, 4 and 6 were injected with pNaKtide, (intraperitoneal dose of 25-mg/kg, every 7 days for 8 weeks). Tissues from liver, kidney, and heart were evaluated markers of aging and Na/K-ATPase signaling activation.

Results

Fibroblasts exposed to oxidative stress underwent oxidation-induced senescence and had increased levels of senescence markers, cell injury, apoptosis, and Na/K-ATPase signaling activation. Treatment with pNaKtide significantly reversed those levels. Levels of aging markers and oxidant stress in old mice were higher than those of young mice. Among cardiac and adipose tissues, senescence, apoptosis and oxidant stress were exacerbated in old mice and even more so when fed WD. pNaKtide treatment significantly reversed levels of aging markers in old mice regardless of diet.

Conclusion

These data show that Na/K-ATPase signaling is intimately involved in the aging process and may serve as a target for anti-aging interventions. pNaKtide inhibited amplification of the oxidant signalling via blocking the Na/K-ATPase pump thus alleviating genetic and phenotypic attributes of aging. pNaKtide holds potential as a novel drug for treating cellular damage that contributes to manifestations of aging and WD.

Funding

  • Other NIH Support