Dietary K+ and Cl− independently regulate basolateral conductance in principal and intercalated cells of the collecting duct
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The renal collecting duct contains two distinct cell types, principal and intercalated cells, expressing potassium Kir4.1/5.1 (KCNJ10/16) and chloride ClC-K2 (ClC-Kb in humans) channels on their basolateral membrane, respectively. Both channels are thought to play important roles in controlling systemic water-electrolyte balance and blood pressure. However, little is known about mechanisms regulating activity of Kir4.1/5.1 and ClC-K2/b. Here, we employed patch clamp analysis at the single channel and whole cell levels in freshly isolated mouse collecting ducts to investigate regulation of Kir4.1/5.1 and ClC-K2/b by dietary K+ and Cl− intake. Treatment of mice with high K+ and high Cl− diet (6% K+, 5% Cl−) for 1 week significantly increased basolateral K+-selective current, single channel Kir4.1/5.1 activity and induced hyperpolarization of basolateral membrane potential in principal cells when compared to values in mice on a regular diet (0.9% K+, 0.5% Cl−). In contrast, basolateral Cl−-selective current and single channel ClC-K2/b activity was markedly decreased in intercalated cells under this condition. Substitution of dietary K+ to Na+ in the presence of high Cl− exerted a similar inhibiting action of ClC-K2/b suggesting that the channel is sensitive to variations in dietary Cl− per se. Cl−-sensitive with-no-lysine kinase (WNK) cascade has been recently proposed to orchestrate electrolyte transport in the distal tubule during variations of dietary K+. However, co-expression of WNK1 or its major downstream effector Ste20-related proline-alanine-rich kinase (SPAK) had no effect on ClC-Kb over-expressed in Chinese hamster ovary (CHO) cells. Treatment of mice with high K+ diet without concomitant elevations in dietary Cl− (6% K+, 0.5% Cl−) elicited a comparable increase in basolateral K+-selective current, single channel Kir4.1/5.1 activity in principal cells, but had no significant effect on ClC-K2/b activity in intercalated cells. Furthermore, stimulation of aldosterone signaling by Deoxycorticosterone acetate (DOCA) recapitulated the stimulatory actions of high K+ intake on Kir4.1/5.1 channels in principal cells but was ineffective to alter ClC-K2/b activity and basolateral Cl− conductance in intercalated cells. In summary, we report that variations of dietary K+ and Cl− independently regulate basolateral potassium and chloride conductance in principal and intercalated cells. We propose that such discrete mechanism might contribute to fine-tuning of urinary excretion of electrolytes depending on dietary intake.
KeywordsKir4.1/5.1 ClC-K2/b Principal and intercalated cells WNK Aldosterone Distal tubule transport
This research was supported by NIH-NIDDK DK095029 (to O. P.), AHA 17GRNT33660488 (to O. P.), NIH-NIDDK DK098145 (to A.R.S.), and ASN Ben J. Lipps Research Fellowship (to V. T.).
Compliance with ethical standards
Animal use and welfare adhered to the NIH Guide for the Care and Use of Laboratory Animals following protocols reviewed and approved by the Animal Care and Use Committees of the University of Texas Health Science Center at Houston.
Conflict of interest
The authors declare that they have no conflict of interest.
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