Aquaporin-1 and sodium-hydrogen exchangers as pharmacological targets in diabetic atherosclerosis

Sodium-hydrogen exchangers (NHEs) and aquaporins (AQPs) are key regulators of cell volume and intracellular ions both in physiological and pathological conditions. By directly affecting water and ion exchanges across the plasma membrane, NHEs and AQPs, particularly isoforms 1, can also influence vascular tone and the cytoskeleton, respectively, in response to several types of stimuli, such as hypertonic stress. NHE-1 and AQP1 are mainly expressed in tissues of the cardiovascular system. Their excessive activation in response to elevated extracellular osmolarity, as occurring in diabetic hyperglycemia, can be deleterious both for micro- and macrovascular endothelial cells. Although NHE-1 and AQP1 regulate the intracellular volume and ions, they also influence the activation of hypertonicity-responsive genes and cell functions involved in glucotoxicity and vascular injury. Because of the involvement of NHEs and AQPs in micro- and macrovascular disease, including arterial hypertension and atherosclerotic plaque destabilization, research has focused on developing inhibitors of these transporters. We here review current knowledge of NHEs and AQPs investigating biological aspects and mechanisms of their regulation, including their potential as target for developing new drugs that could target diabetic atherosclerosis.