Revisiting voltage-coupled H+secretion in the collecting duct

Experimental studies have shown that V-type ATPase-driven H+secretion is dependent on the transepithelial voltage. On this basis the "voltage hypothesis" of urinary acidification by the collecting duct was derived. Accordingly, it has been supposed that the lumen-negative potential created by the reabsorption of Na+via the epithelial sodium channel (ENaC) enhances electrogenic H+secretion via the V-type H+-ATPase. This concept continues to be widely used to explain acid/base disorders. Importantly, however, a solid proof-of-principle for the voltage hypothesis in physiologically relevant situations has not been reached. Rather, it has been challenged by recent in vivofunctional studies. In this review we outline the arguments and experimental observations explaining why voltage-coupled H+secretion in the collecting duct often appears poorly applicable to rationalize for changes of H+secretion as a function of more or less ENaC function in the collecting duct.