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Kir4.1 is a potassium (K) sensor and mediates the effect of dietary K intake on NCC activity in the distal convoluted tubule (DCT)
Author(s) -
Su XiaoTong,
Gallardo Catherina Cuevas,
Wang MingXiao,
Wu Peng,
Gao Zhongxiuzi,
Lin DaoHong,
McCormick James A.,
Yang ChaoLing,
Ellison David H.,
Wang WenHui
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.857.1
Subject(s) - distal convoluted tubule , chemistry , cotransporter , endocrinology , medicine , potassium channel , reabsorption , kidney , sodium , biology , organic chemistry
Recent paradigm‐shifting discoveries concerning the control of systemic K balance have highlighted the key role played by the thiazide‐sensitive sodium chloride cotransporter (NCC) along the DCT. Thus, a high K (HK) intake‐induced inhibition of NCC should increase Na and volume delivery to the aldosterone‐sensitive distal nephron (ASDN) thereby stimulating K secretion, whereas a low K intake‐induced stimulation of NCC should have the opposite effect. However, the mechanism by which dietary K intake regulates NCC activity is not completely understood. We have previously demonstrated that Kir4.1 activity determines NCC activity, since renal deletion of Kir4.1 inhibited the expression of total NCC (tNCC) and phosphorylated‐NCC (pNCC) by inhibiting with‐no‐lysine kinase (WNK) and ste20‐proline‐alanine‐rich kinase (SPAK). The aim of the present study was to test the hypothesis that Kir4.1 is essential for mediating the effect of dietary K intake on NCC by using Kcnj10 fl/fl (Con) and inducible kidney‐specific Kcnj10 (Kir4.1) knockout mice (KS‐Kir4.1 KO). Patch‐clamp experiments show that HK intake significantly decreases the Barium‐sensitive whole‐cell K currents in early DCT (DCT1) from 1300 pA to 500 pA and depolarizes the membrane from −62 mV to −40 mV. Since Kir4.1/Kir5.1 heterotetramer is the only K channel in the DCT1, this suggests that HK intake inhibits Kir4.1. This notion is supported by the observation that HK intake not only decreases the probability of finding Kir4.1 in the DCT but also channel activity (defined by NP o ). In contrast, low K intake increased the whole‐cell K currents to 2300 pA and hyperpolarizes the membrane to −77 mV in the DCT1. We also confirmed that HK intake decreases whereas low K intake increases the abundance of tNCC and pNCC. Disruption of Kir4.1 not only eliminated the basolateral K conductance of the DCT under control conditions, but also completely abolished the effect of dietary K intake on K conductance and membrane potential along the DCT. Moreover, the regulatory effect of dietary K intake on the expression of tNCC and pNCC was completely absent in KS‐Kir4.1 KO mice. Renal clearance studies demonstrated that HCTZ‐induced natriuretic effect is inhibited in WT mice on HK diet whereas it is stimulated in the WT mice on low K diet. Disruption of Kir4.1 significantly increased the basal level of Na excretion. Moreover, the natriuretic effect of HCTZ was completely absent in KS‐Kir4.1 KO mice, suggesting a loss of NCC function. In summary, we demonstrated that HK intake inhibits Kir4.1 in the basolateral membrane of the DCT, causing membrane depolarization which is expected to inhibit the Cl‐sensitive WNK‐SPAK pathway. In contrast, low K intake stimulates Kir4.1 and hyperpolarizes the membrane of the DCT thereby activating this pathway. We conclude that Kir4.1 serves as a K sensor in the DCT and plays an essential role in mediating the effect of dietary K intake on NCC activity. Support or Funding Information National Institutes of Health Grant DK54983.