RESUMO
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.
Assuntos
Envelhecimento/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/efeitos da radiação , Envelhecimento/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Apoptose/efeitos da radiação , Western Blotting , Caspase 9/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Ecocardiografia , Marcação In Situ das Extremidades Cortadas , L-Lactato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ouabaína/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Estresse Oxidativo/efeitos da radiação , Carbonilação Proteica/efeitos dos fármacos , Carbonilação Proteica/efeitos da radiação , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos da radiação , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Raios Ultravioleta , Vitamina E/farmacologia , Água/metabolismoRESUMO
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.