Coupling of epithelial Na and Cl channels by direct and indirect activation by serine proteases

mammalian collecting duct (CD) is continuously exposed to urinary proteases. The CD expresses an epithelial Na channel (ENaC) that is activated after cleavage by serine proteases. ENaC also exists at the plasma membrane in the uncleaved form, rendering activation by extracellular proteases an important mechanism for regulating Na transport. Many exogenous and a small number of endogenous extra-cellular serine proteases have been shown to activate the channel. Recently, kallikrein 1 (KLK1) was shown to increase ENaC cleav-age in the native CD indicating a possible direct role of this endog-enous protease in Na homeostasis. To explore this process, we examined the coordinated effect of this protease on Na and Cl transport in a polarized renal epithelial cell line (Madin-Darby canine kidney). We also examined the role of native urinary proteases in this process. Short-circuit current (Isc) was used to measure transport of these ions. The Isc exhibited an ENaC-dependent Na component tha