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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Ketchum, Christian J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York Medical College
Schools of Medicine
United States
Zip Code
Dong, Ke; Yan, Qingshang; Lu, Ming et al. (2016) Romk1 Knockout Mice Do Not Produce Bartter Phenotype but Exhibit Impaired K Excretion. J Biol Chem 291:5259-69
Wang, Wen-Hui (2016) Basolateral Kir4.1 activity in the distal convoluted tubule regulates K secretion by determining NaCl cotransporter activity. Curr Opin Nephrol Hypertens 25:429-35
Fan, Lili; Wang, Xiaoyan; Zhang, Dandan et al. (2015) Vasopressin-induced stimulation of the Na(+)-activated K(+) channels is responsible for maintaining the basolateral K(+) conductance of the thick ascending limb (TAL) in EAST/SeSAME syndrome. Biochim Biophys Acta 1852:2554-62
Wang, Lijun; Zhang, Chengbiao; Su, Xiaotong et al. (2015) Caveolin-1 Deficiency Inhibits the Basolateral K+ Channels in the Distal Convoluted Tubule and Impairs Renal K+ and Mg2+ Transport. J Am Soc Nephrol 26:2678-90
Terker, Andrew S; Zhang, Chong; McCormick, James A et al. (2015) Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride. Cell Metab 21:39-50
Lin, Dao-Hong; Yue, Peng; Yarborough 3rd, Orlando et al. (2015) Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK). Proc Natl Acad Sci U S A 112:4495-500
Ellison, David H; Terker, Andrew S (2015) Why Your Mother Was Right: How Potassium Intake Reduces Blood Pressure. Trans Am Clin Climatol Assoc 126:46-55
Zhang, Chengbiao; Wang, Lijun; Su, Xiao-Tong et al. (2015) KCNJ10 (Kir4.1) is expressed in the basolateral membrane of the cortical thick ascending limb. Am J Physiol Renal Physiol 308:F1288-96
Wang, Mingxiao; Luan, Haiyan; Wu, Peng et al. (2014) Angiotensin II stimulates basolateral 50-pS K channels in the thick ascending limb. Am J Physiol Renal Physiol 306:F509-16
Wei, Yuan; Liao, Yi; Zavilowitz, Beth et al. (2014) Angiotensin II type 2 receptor regulates ROMK-like K⁺ channel activity in the renal cortical collecting duct during high dietary K⁺ adaptation. Am J Physiol Renal Physiol 307:F833-43

Showing the most recent 10 out of 60 publications