Regulation of basolateral ClC‐K2‐dependent Cl‐ reabsorption in collecting duct intercalated cells by dietary electrolyte intake and Ang II

Abstract

Hypertension is the major clinically relevant problem, which commonly stems from excessive renal salt retention. Both basic and clinical studies show that elevated dietary Na+ can promote volume expansion and increased blood pressure only when accompanied with high Cl−. The collecting duct (CD) is the only tubular segment with capacity to separately reabsorb Na+ and Cl−. Here, principal cells perform electrogenic Na+ reabsorption via the epithelial Na+ channel (ENaC), whereas activity of the basolateral ClC‐K2 chloride channel mediates trans‐cellular Clmovement in electrically uncoupled intercalated cells. In contrast to ENaC, little is known about dietary and hormonal means controlling ClC‐K2 activity in the CD. Using patch clamp electrophysiology at both single channel and macroscopic levels in freshly isolated CDs, we found that ClC‐K2 single channel activity and macroscopic Cl− conductance in intercalated cells are inversely related to dietary Cl−, but not K+ intake. Furthermore, stimulation of mineralocorticoid receptors with deoxycorticosterone acetate (DOCA) failed to affect ClC‐K2 activity arguing against a role of aldosterone in regulation of ClC‐K2 by dietary Cl−. In contrast, Angiotensin II (Ang II) exerts a set of stimulatory actions by acutely increasing ClC‐K2 single channel open probability, ClC‐K2/b‐dependent Cl− conductance in ICs and on a longer timescale promotes ClC‐K2/b trafficking to the basolateral membrane of ICs in freshly isolated CDs implicating its potential role during variations in dietary Cl− intake. Inhibition of AT1 receptors (AT1R) with losartan precluded regulation of ClC‐K2 by Ang II. Moreover, ClC‐K2 abundance was significantly reduced in mice lacking AT1R. Overall, our results point to a critical role of dietary Cl− in controlling ClC‐K2 activity in the CD likely in an Ang II‐AT1R dependent manner. We propose that this mechanism could be instrumental for the discrete CD responses to hypovolemia (when Ang II is high) and hyperkalemia (Ang II is low).Support or Funding InformationThis research was supported by NIH‐NIDDK DK095029 (to O. P.), AHA 17GRNT33660488 (to O. P.), and ASN Ben J. Lipps Research Fellowship (to V. T.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.