Renal defects in KCNE1 knockout mice are mimicked by chromanol 293B in vivo: Identification of a KCNE1-regulated K + conductance in the proximal tubule

The kidney plays a critical role in regulating body fluid volume and blood pressure by conserving ions, solutes and water. Knowing the processes that underpin the handling of ions, solutes and water by the kidney is essential to our understanding of fluid and blood pressure regulation. Movement of ions is mediated by specific transport proteins found in the membranes of kidney cells. These proteins are regulated by additional proteins, called accessory proteins. In the current study, we have examined the role of the accessory protein KCNE1 in regulating a channel, KCNQ1, which is important in kidney function. We have observed that in the absence of KCNE1 the kidney has difficulty conserving sodium, chloride and water. However, by using specific inhibitors of these proteins we have also determined that although KCNE1 has a role in kidney function, the mechanism of its action is unlikely to be by regulating the protein KCNQ1. Abstract KCNE1 is a protein of low molecular mass that is known to regulate the chromanol 293B and clofilium-sensitive K + channel, KCNQ1, in a number of tissues. Previous work on the kidney of KCNE1 and KCNQ1 knockout mice has revealed that these animals have different renal phenotypes, suggesting that KCNE1 may not regulate KCNQ1 in the renal system. In the current study, in vivo clearance approaches and whole cell voltage-clamp recordings from isolated renal proximal tubules were used to examine the physiological role of KCNE1. Data from wild-type mice were compared to those from KCNE1 knockout mice. In clearance studies the KCNE1 knockout mice had an increased fractional excretion of Na +, Cl -, HCO 3 - and water. This profile was mimicked in wild-type mice by infusion of chromanol 293B, while chromanol was without effect in KCNE1 knockout animals. Clofilium also increased the fractional excretion of Na +, Cl - and water, but this was observed in both wild-type and knockout mice, suggesting that KCNE1 was regulating a chromanol-sensitive but clofilium-insensitive pathway. In whole cell voltage clamp recordings from proximal tubules, a chromanol-sensitive, K +-selective conductance was identified that was absent in tubules from knockout animals. The properties of this conductance were not consistent with its being mediated by KCNQ1, suggesting that KCNE1 regulates another K + channel in the renal proximal tubule. Taken together these data suggest that KCNE1 regulates a K +-selective conductance in the renal proximal tubule that plays a relatively minor role in driving the transport of Na +, Cl - and HCO 3 -. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.