Molecular mechanisms

The clinically useful and potent distal acting diuretics enhance urinary NaCl excretion by specific inhibition of distinct sodium transport processes in the loop of Henle and distal nephron. When these compounds were first used as diuretics little was known about their cellular mechanisms of action. Physiological investigations over the past 25 years, however, have shown that each class of diuretics inhibits a specific ion transport system in the kidney. Over the past few years, the molecular cloning of the distal diuretic-sensitive Na+ transporters has significantly enhanced our understanding of the mechanism of action of each class of diuretics and has clearly defined the specific protein (and its gene) that is the target for each of these diuretics. The identification of mutations in the genes encoding these transporters in inherited disorders characterized by alterations in salt balance has provided unequivocal evidence for roles of the cloned diuretic-sensitive transporters in sodium homeostasis. Many laboratories are actively engaged in defining the structural sites for ion transport and diuretic binding, and the molecular mechanisms of transport regulation. This information may enable the design of new diuretics and provide the basis for improved use of diuretics. This review will focus on this recent molecular information.