Chapter 19 - The Syndrome of Hypertension and Hyperkalemia (Pseudohypoaldosteronism Type II): WNK Kinases Regulate the Balance Between Renal Salt Reabsorption and Potassium Secretion

Abstract

The molecular genetic discovery that mutations in WNK1 and WNK4 cause pseudohypoaldosteronism type II (PHAII), has unraveled the complex mechanism by which the kidney regulates the balance between salt reabsorption and potassium secretion. Logical targets include the sodium and chloride reabsorption pathways mediated by Na-Cl cotransporter (NCC) and epithelial sodium channel (ENaC), the mediators and regulators of distal nephron potassium secretion, including renal outer medullary potassium channel (ROMK), the BK potassium channel, and ENaC, the paracellular chloride flux pathway, and the apical H+-ATPase involved in distal proton secretion. The marked impairment in renal potassium secretion is the most consistent feature of PHAII and suggests several potential targets. The potassium channel ROMK is the major mediator of renal potassium secretion in the connecting tubule (CNT)/CCD under normal circumstances and is one possible target of WNK4. ENaC, the major pathway for electrogenic sodium reabsorption in the CNT and CCD, is another potential target of the WNKs. ENaC activity produces the lumen-negative potential and is required for normal potassium secretion, as revealed by inherited and acquired alteration in ENaC activity. States featuring increased ENaC activity often cause hypokalemia owing to the increased lumen-negative potential but mutations that result in loss of ENaC function lead to impaired production of a lumen-negative potential and often profound hyperkalemia.