Maintenance of extracellular potassium (K) in a normal range is essential for the function of cardiac myocytes, skeletal muscle and neurons. Hyperkalemia or hypokalemia is known to cause cardiac arrhythmias and to interfere with normal neuron function and muscle contraction. The aldosterone-sensitive distal nephron (ASDN) including the late distal convoluted tubule (DCT), connecting tubule (CNT) and cortical collecting duct (CCD) is responsible for K secretion. We previously demonstrated that the depletion Kir.4.1 in the DCT inhibited the expression of NCC which plays an important role in regulating renal K homeostasis. Kir.4.1 is expressed in the DCT, CNT and CCD. Loss-of-function mutations of Kcnj10 cause EAST/SeSAME syndrome in humans (seizures, sensorineural deafness, ataxia, mental retardation and electrolyte imbalance). The renal phenotype of the disease includes hypomagnesemia, hypokalemia and metabolic alkalosis, suggesting that the disruption of Kir4.1 mainly impairs the transport in the DCT. The role of Kir.4.1 in the regulation of renal K secretion is also strongly suggested by our preliminary data showing that a High K (HK) intake inhibits the basolateral K channels in the DCT while a low K (LK) stimulates the basolateral K channels. We will test two hypotheses: 1) The stimulation of Kir4.1 in the DCT is necessary for inhibiting K secretion during hypokalemia by activating NCC and suppressing ROMK and ENaC thereby switching the function of DCT2 to DCT1; 2) The inhibition of Kir4.1 in the DCT is essential for stimulating K secretion during hyperkalemia by inhibiting NCC and stimulating ROMK and ENaC thereby switching the function of DCT2 to CNT. The hypothesis is based on the following observations made in previous and preliminary experiments: 1) Kir.4.1 is a major type of K channel in the basolateral membrane of the DCT; 2) The disruption of Kir.4.1 abolishes the basolateral K conductance, depolarizes cell membrane and inhibits the Cl conductance in the DCT; 3) The down-regulation of Kir.4.1 decreases NCC expression and activity in inducible kidney specific Kcnj10 knockout mice (KS-Kcnj10 KO); 4) LK intake increases the negativity of the membrane potential (hyperpolarization) in the DCT, indicating a positive correlation between Kir.4.1 and NCC activity; 5) LK-induced stimulation of NCC expression is abolished in KS-Kcnj10 KO; 6) ROMK channel activity in DCT2/CNT of KS-Kcnj10 KO mice is higher than those of WT despite hypokalemia. Therefore, the preliminary data strongly suggest the role of Kir.4.1 in regulating Na and K transport in the DCT in response to dietary K intake.
In Aim 1, we will test whether Kir.4.1 activity in the DCT determines NCC expression, phosphorylation and activity via intracellular Cl (Cli)-sensitive mechanism.
In Aim 2, we will test whether LK intake-induced stimulation of Kir4.1 is essential for activating NCC and inhibiting ENaC and ROMK in DCT2 thereby suppressing K secretion in the DCT.
In Aim 3, we will test whether HK intake-induced inhibition of Kir4.1 is essential for inactivating NCC and stimulating ENaC and ROMK in DCT2 thereby stimulating K secretion in the DCT.

Public Health Relevance

Hyperkalemia, a potentially fatal disorder, occurs commonly in the setting of chronic kidney disease and heart failure. Its incidence appears to have increased, because the most effective cardio- and reno-protective drugs, agents that block the renin/angiotensin/aldosterone system (RAAS), all impair renal K disposition. We have now identified a novel mechanism by which the kidney can sense the change in dietary K content and regulate K excretion or absorption. The new concept will expend the current knowledge regarding renal K transport and may lead to development of new approach for treatment of hypokalemia and hyperkalemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054983-18
Application #
9717235
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ketchum, Christian J
Project Start
2016-08-29
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
18
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Zhang, Dan-Dan; Gao, Zhong-Xiuzi; Vio, Carlos P et al. (2018) Bradykinin Stimulates Renal Na+ and K+ Excretion by Inhibiting the K+ Channel (Kir4.1) in the Distal Convoluted Tubule. Hypertension 72:361-369
Terker, Andrew S; Castañeda-Bueno, Maria; Ferdaus, Mohammed Z et al. (2018) With no lysine kinase 4 modulates sodium potassium 2 chloride cotransporter activity in vivo. Am J Physiol Renal Physiol 315:F781-F790
Wu, Peng; Gao, Zhong-Xiuzi; Duan, Xin-Peng et al. (2018) AT2R (Angiotensin II Type 2 Receptor)-Mediated Regulation of NCC (Na-Cl Cotransporter) and Renal K Excretion Depends on the K Channel, Kir4.1. Hypertension 71:622-630
Wang, Lijun; Zhang, Chengbiao; Su, Xiao-Tong et al. (2017) PGF2?regulates the basolateral K channels in the distal convoluted tubule. Am J Physiol Renal Physiol 313:F254-F261
Scholl, Ute I; Abriola, Laura; Zhang, Chengbiao et al. (2017) Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma. J Clin Invest 127:2739-2750
Pandey, Varunkumar; Garcia, Victor; Gilani, Ankit et al. (2017) The Blood Pressure-Lowering Effect of 20-HETE Blockade in Cyp4a14(-/-) Mice Is Associated with Natriuresis. J Pharmacol Exp Ther 363:412-418
Ellison, David H; Felker, G Michael (2017) Diuretic Treatment in Heart Failure. N Engl J Med 377:1964-1975
Carrisoza-Gaytán, Rolando; Wang, Lijun; Schreck, Carlos et al. (2017) The mechanosensitive BK?/?1 channel localizes to cilia of principal cells in rabbit cortical collecting duct (CCD). Am J Physiol Renal Physiol 312:F143-F156
Ellison, David H (2017) Treatment of Disorders of Sodium Balance in Chronic Kidney Disease. Adv Chronic Kidney Dis 24:332-341
Cuevas, Catherina A; Su, Xiao-Tong; Wang, Ming-Xiao et al. (2017) Potassium Sensing by Renal Distal Tubules Requires Kir4.1. J Am Soc Nephrol 28:1814-1825

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