Bartter/Gitelman syndromes as a model to study systemic oxidative stress in humans

Reactive oxygen species (ROS) are intermediates in reduction-oxidation reactions that begin with the addition of one electron to molecular oxygen, generating the primary ROS superoxide, which in turn interacts with other molecules to produce secondary ROS, such as hydrogen peroxide, hydroxyl radical, and peroxynitrite. ROS are continuously produced during metabolic processes and are deemed to play an important role in cardiovascular diseases, namely, myocardial hypertrophy and fibrosis and atherosclerosis, via oxidative damage of lipids, proteins, and deoxyribonucleic acid. Angiotensin II (Ang II) is a potent vasoactive agent that also exerts mitogenic, proinflammatory, and profibrotic effects through several signaling pathways, in part involving ROS, particularly superoxide and hydrogen peroxide. Moreover, Ang II stimulates NADPH oxidases, leading to higher ROS generation and oxidative stress. Bartter/Gitelman syndrome patients, despite elevated plasma renin activity, Ang II, and aldosterone levels, exhibit reduced peripheral resistance, normal/low blood pressure, and blunted pressor effect of vasoconstrictors. In addition, notwithstanding the activation of the renin-angiotensin system and the increased plasma levels of Ang II, these patients display decreased production of ROS, reduced oxidative stress, and increased antioxidant defenses. In fact, Bartter/Gitelman syndrome patients are characterized by reduced levels of p22phox gene expression and undetectable plasma peroxynitrite levels, while showing increased plasma antioxidant power and expression of antioxidant enzymes, such as heme oxygenase-1. In conclusion, multifarious data suggest that Bartter and Gitelman syndrome patients are a model of low oxidative stress and high antioxidant defenses. The contribution offered by the study of these syndromes in elucidating the molecular mechanisms underlying this favorable status could offer chances for new therapeutic targets in disease characterized by high levels of reactive oxygen species.