3. Conclusions

A plethora of experimental evidence indicates that ROS are important upstream regulators of the expression, secretion and/or activity of RAAS components. The majority of the referred studies suggests that under conditions of increased ROS availability there is an enhanced RAAS activation that is attenuated or abolished by treatment with antioxidants or inhibitors of ROS production. Nevertheless, there are also some reports of negative regulation of RAAS constituents by oxidant species that might serve as physiological protective mechanisms limiting the overactivation of this system and consequent deleterious effects on cell and organ functions. Importantly, in experimental pathological conditions associated with increased oxidative stress, such as arterial hypertension, obesity, diabetes, heart failure and renal disease, ROS have been shown to promote RAAS upregulation, thereby inducing a positive feedback loop that aggravates the cardiometabolic and/or renal injury. Currently, there is a lack of clinical studies evaluating the impact of the manipulation of ROS levels by antioxidants or inhibitors of ROS production on the expression, secretion and activity of RAAS components. The elucidation of the role of ROS in the regulation of RAAS in human physiological and pathological conditions, as well as the development of dual antioxidant-cardiovascular acting drugs and comparison of their clinical efficacy over currently used agents, would be important to improve the therapeutic strategies for many pathologies for which the blockade of RAAS appears to be insufficient to prevent disease-associated morbidity and mortality due to the existence of escape mechanisms.
