ABSTRACT
As aging involves oxidant injury, we examined the role of the recently described Na/K-ATPase oxidant amplification loop (NKAL). First, C57Bl6 old mice were given a western diet to stimulate oxidant injury or pNaKtide to antagonize the NKAL. The western diet accelerated functional and morphological evidence for aging whereas pNaKtide attenuated these changes. Next, human dermal fibroblasts (HDFs) were exposed to different types of oxidant stress in vitro each of which increased expression of senescence markers, cell-injury, and apoptosis as well as stimulated the NKAL. Further stimulation of the NKAL with ouabain augmented cellular senescence whereas treatment with pNaKtide attenuated it. Although N-Acetyl Cysteine and Vitamin E also ameliorated overall oxidant stress to a similar degree as pNaKtide, the pNaKtide produced protection against senescence that was substantially greater than that seen with either antioxidant. In particular, pNaKtide appeared to specifically ameliorate nuclear oxidant stress to a greater degree. These data demonstrate that the NKAL is intimately involved in the aging process and may serve as a target for anti-aging interventions.
Subject(s)
Aging/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Adipose Tissue/radiation effects , Aging/genetics , Animals , Apoptosis/drug effects , Apoptosis/physiology , Apoptosis/radiation effects , Blotting, Western , Caspase 9/metabolism , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Cell Survival/drug effects , Cell Survival/radiation effects , DNA Damage/drug effects , DNA Damage/radiation effects , Echocardiography , In Situ Nick-End Labeling , L-Lactate Dehydrogenase/metabolism , Male , Mice , Mice, Inbred C57BL , Ouabain/pharmacology , Oxidative Stress/drug effects , Oxidative Stress/genetics , Oxidative Stress/radiation effects , Protein Carbonylation/drug effects , Protein Carbonylation/radiation effects , Real-Time Polymerase Chain Reaction , Signal Transduction/physiology , Signal Transduction/radiation effects , Thiobarbituric Acid Reactive Substances/metabolism , Ultraviolet Rays , Vitamin E/pharmacology , Water/metabolismABSTRACT
Renal and cardiac function are greatly affected by chronic oxidative stress which can cause many pathophysiological states. The Na/K-ATPase is well-described as an ion pumping enzyme involved in maintaining cellular ion homeostasis; however, in the past two decades, extensive research has been done to understand the signaling function of the Na/K-ATPase and determine its role in physiological and pathophysiological states. Our lab has shown that the Na/K-ATPase signaling cascade can function as an amplifier of reactive oxygen species (ROS) which can be initiated by cardiotonic steroids or increases in ROS. Regulation of systemic oxidative stress by targeting Na/K-ATPase signaling mediated oxidant amplification improves 5/6th partial nephrectomy (PNx) mediated uremic cardiomyopathy, renal sodium handling, as well as ameliorates adipogenesis. This review will present this new concept of Na/K-ATPase signaling mediated oxidant amplification loop and its clinic implication.
