Fig. 3
From: The WNK signaling pathway and salt-sensitive hypertension
Aberrant activation of the with-no-lysine kinase (WNK)–oxidative stress-responsive gene 1 (OSR1)/STE20-related proline/alanine-rich kinase (SPAK)–sodium chloride cotransporter (NCC) phosphorylation cascade causes salt-sensitive hypertension in PHAII. All PHAII-causing mutations of WNK4, Kelch-like 3 (KLHL3), and Cullin 3 (CUL3) result in defective degradation of WNK kinases. On the other hand, mutation of WNK1 causes increased transcription and protein expression. Accordingly, accumulated WNK kinase protein activates the OSR1/SPAK–NCC phosphorylation cascade and increases sodium reabsorption. The activated WNK signaling pathway is not properly suppressed by a high salt diet, leading to salt-sensitive hypertension. Enhanced sodium reabsorption at the distal convoluted tubule (DCT) decreases sodium delivery to the downstream cortical collecting ducts (CCDs). Given that sodium reabsorption through the epithelial sodium channels (ENaCs) in the CCDs are electrically coupled with potassium excretion through the renal outer membrane potassium channel (ROMK), decreased sodium delivery results in potassium retention and hyperkalemia in PHAII patients
