With-No-Lysine Kinase 4 (WNK4) plays an important role in regulating Na and K transport in the aldosterone-sensitive distal nephron (ASDN). Mutation of WNK4 causes familial hyperkalemic hypertension, an autosomal dominant disease characterized by salt-sensitive hypertension, hyperkalemia and renal tubule acidosis (Pseudohypoaldosteronism type II). A large body of evidence shows that WNK4 inhibits ROMK, regulates ENaC and modulates the paracellular Cl permeability in the collecting duct. The inhibitory effect of WNK4 on ROMK is attenuated by serum-glucocorticoid- induced kinase1 (SGK1)-mediated phosphorylation of WNK4 in the """"""""switch-domain"""""""". Recently, we have further demonstrated that Src-family protein tyrosine kinases (SFK), such as c-Src, phosphorylates WNK4 and diminishes SGK1-induced phosphorylation of WNK4 thereby restoring the inhibitory effect of WNK4 on ROMK channels. The interaction among WNK4, SFK and SGK1 plays an important role in stimulating K secretion during increasing K intake and in preventing K loss during volume depletion. However, the molecular mechanism by which c-Src modulates the interaction of SGK1 with WNK4 is not understood. The goal of the present proposal is to test the hypothesis that SFK-mediated phosphorylation of WNK4 activates protein phosphatase 1 (PP1) thereby abolishing the SGK1-induced stimulation of WNK4 phosphorylation and restoring the inhibitory effect of WNK4 on ROMK1.
Specific Aim 1 is to test the hypothesis that c-Src binds and phosphorylates WNK4 and that the Tyr phosphorylation of WNK4 abolishes SGK1-induced phosphorylation at WNK4's switch domain thereby locking WNK4 in inhibitory mode for ROMK.
Specific Aim 2 is to test the hypothesis that PP1 binds to WNK4 and is involved in mediating the effect of c-Src on WNK4-induced inhibition of ROMK.
Specific Aim 3 is to test the hypothesis that PTP1D binds to WNK4, modulates PP1 activity and participates in the interaction among SGK1, WNK4 and c- Src, a mechanism which specifically regulates ROMK but has no effect on ENaC. The significance of the project is to expand the current understanding regarding the regulation of Na and K transport in the ASDN and to provide an integrated mechanism of WNK4-mediated regulation of ROMK in the ASDN.
Disturbance in renal potassium (K) results in hyperkalemia or hypokalemia which could lead to cardiac arrhythmia whereas disturbance in renal sodium (Na) absorption leads to hypertension or hypotension. Although increasing renal Na transport is usually coupled with enhanced K excretion, Na transport is sometimes dissociated with K secretion in the kidney. However, the underlying mechanism is not completely clear. We have identified a novel mechanism by which renal Na absorption is decoupled with renal K secretion. The new concept will expend the current knowledge regarding renal K and Na transport and shed a light into the mechanism of familial hyperkalemic hypertension , a disease also known as pseudohypoaldosteronism type 2.
|Ellison, David H; Felker, G Michael (2017) Diuretic Treatment in Heart Failure. N Engl J Med 377:1964-1975|
|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|
|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|
|Ellison, David H (2017) Treatment of Disorders of Sodium Balance in Chronic Kidney Disease. Adv Chronic Kidney Dis 24:332-341|
|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|
|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|
|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|
|Su, Xiao-Tong; Zhang, Chengbiao; Wang, Lijun et al. (2016) Disruption of KCNJ10 (Kir4.1) stimulates the expression of ENaC in the collecting duct. Am J Physiol Renal Physiol 310:F985-93|
|Su, Xiao-Tong; Wang, Wen-Hui (2016) The expression, regulation, and function of Kir4.1 (Kcnj10) in the mammalian kidney. Am J Physiol Renal Physiol 311:F12-5|
|Zhang, Chengbiao; Su, Xiaotong; Bellner, Lars et al. (2016) Caveolin-1 regulates corneal wound healing by modulating Kir4.1 activity. Am J Physiol Cell Physiol 310:C993-C1000|
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