The kidney adjusts K+ secretion in the distal nephron in response to variations in dietary intake to maintain K+ homeostasis. The distal K+ secretion involves K+ efflux from the cell into the lumen through apical K+ channels such as ROMK. Na+ reabsorption via the epithelial Na+ channel ENaC provides the electrical driving force for K+ secretion. An increase in the activity of the Na-Cl cotransporter NCC may decrease Na+ delivery to ENaC thus diminishing K+ secretion. In support for the role of NCC as well as ROMK in maintaining K+ homeostasis during dietary variations of K+ intake, high K+ loading in rodents increases the density of ROMK while decreasing the density of NCC in the distal nephron. The upstream regulation of ROMK and NCC remains incompletely understood. WNK1 is a protein kinase of which gene mutations resulting in increased expression cause pseudohypoaldosteronism type II (PHA2), an autosomal-dominant disease characterized by hypertension and hyperkalemia. WNK1 has several alternatively spliced variants including a ubiquitous full- length long WNK1 (L-WNK1) and a shorter kidney-specific WNK1 (KS-WNK1). Cell-based expression studies have shown that L-WNK1 activates NCC and inhibits ROMK. KS-WNK1, by itself, does not regulate NCC and ROMK but reverses L-WNK1-mediated activation and inhibition of NCC and ROMK, respectively. The long- term goal of our research is to understand K+ homeostasis in the normal physiology and in diseased states. Here, we will examine three specific aims.
Aim 1 is to examine the physiological role and mechanism of L- WNK1 in the regulation of renal Na+ and K+ transport.
Aim 2 is to examine the hypothesis that KS-WNK1 antagonizes L-WNK1 regulation of renal Na+ and K+ transport and changes in dietary K+ affect the ratio of L- over KS-WNK1 to regulate NCC and ROMK.
Aim 3 is to examine the interplay between aldosterone and L- and KS-WNK1 pathway in the regulation of renal Na+ and K+ transport and the response to variations in dietary K+. We have generated mouse models with genetically altered expression of L-and/or KS-WNK1. Renal Na+ and K+ transport in these mice will be studied by measuring blood and urinary electrolytes and expression of Na+ and K+ transporters in response to dietary Na+ or K+ perturbations and to diuretics. K+ secretion will also be studied by in vitro microperfusion of isolated CCD tubules. Surgical adrenalectomy will be performed to examine interactions between aldosterone and WNK1 pathway. These studies will provide important insights to the in vivo role of WNK1 in renal Na+ and K+ transport in the normal physiology and in diseased states.

Public Health Relevance

The kidney plays an important role in regulating blood K levels by controlling urinary excretion. The goal of our research is to understand how the kidney regulates K excretion in the normal physiology and in diseased states. Our research may lead to better understanding of the kidney, heart and muscle diseases and potential new therapy for these diseases.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ketchum, Christian J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Lai, Ju-Geng; Tsai, Su-Mei; Tu, Hsiao-Chen et al. (2014) Zebrafish WNK lysine deficient protein kinase 1 (wnk1) affects angiogenesis associated with VEGF signaling. PLoS One 9:e106129
Wu, Yipin; Schellinger, Jeffrey N; Huang, Chou-Long et al. (2014) Hypotonicity stimulates potassium flux through the WNK-SPAK/OSR1 kinase cascade and the Ncc69 sodium-potassium-2-chloride cotransporter in the Drosophila renal tubule. J Biol Chem 289:26131-42
Cheng, Chih-Jen; Baum, Michel; Huang, Chou-Long (2013) Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct. Am J Physiol Renal Physiol 304:F397-402
Huang, Chou-Long; Moe, Orson W (2013) Clinical assessment of phosphorus status, balance and renal handling in normal individuals and in patients with chronic kidney disease. Curr Opin Nephrol Hypertens 22:452-8
Xie, Jian; Yoon, Joonho; Yang, Sung-Sen et al. (2013) WNK1 protein kinase regulates embryonic cardiovascular development through the OSR1 signaling cascade. J Biol Chem 288:8566-74
Cheng, Chih-Jen; Kuo, Elizabeth; Huang, Chou-Long (2013) Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis. Semin Nephrol 33:237-47
Hedayati, S Susan; Minhajuddin, Abu T; Ijaz, Adeel et al. (2012) Association of urinary sodium/potassium ratio with blood pressure: sex and racial differences. Clin J Am Soc Nephrol 7:315-22
Rodan, Aylin R; Cheng, Chih-Jen; Huang, Chou-Long (2011) Recent advances in distal tubular potassium handling. Am J Physiol Renal Physiol 300:F821-7
Cheng, Chih-Jen; Huang, Chou-Long (2011) Activation of PI3-kinase stimulates endocytosis of ROMK via Akt1/SGK1-dependent phosphorylation of WNK1. J Am Soc Nephrol 22:460-71
Cheng, Chih-Jen; Lin, Shih-Hua; Lo, Yi-Fen et al. (2011) Identification and functional characterization of Kir2.6 mutations associated with non-familial hypokalemic periodic paralysis. J Biol Chem 286:27425-35

Showing the most recent 10 out of 37 publications