Multigene kinase network, kidney transport, and salt in essential hypertension

Abstract

Evidence is mounting that a multi-gene kinase network is central to the regulation of renal Na(+) and K(+) excretion and that aberrant signaling through the pathway can result in renal sodium retention and hypertension (HTN). The kinase network minimally includes the Ste20-related proline-alanine-rich kinase (SPAK), the with-no-lysine kinases (WNKs), WNK4 and WNK1, and their effectors, the thiazide-sensitive NaCl cotransporter and the potassium secretory channel, ROMK. Available evidence indicates that the kinase network normally functions as a switch to change the mineralocorticoid hormone response of the kidney to either conserve sodium or excrete potassium, depending on whether aldosterone is induced by a change in dietary sodium or potassium. Recently, common genetic variants in the SPAK gene have been identified as HTN susceptibility factors in the general population, suggesting that altered WNK-SPAK signaling plays an important role in essential HTN. Here, we highlight recent breakthroughs in this emerging field and discuss areas of consensus and uncertainty.

Figure 1. Model of the WNK/SPAK signal transduction system in the distal nephron

switching the aldosterone response of the kidney to be antinatriuretic (left) or kaliuretic (right). Green arrow heads (activating pathways), red blunt end (inhibitory pathway). Left panel shows the pathway in the setting of low Na+ diet when Ang II and SGK-1 signaling leads to phosphorylation of WNK4. This stimulates phosphorylation of SPAK, which, in turn, phosphorylates NCC, activating Na⁺ transport to enhance conservation of Na⁺ in hypovolemia. Stimulation of unknown receptors are suspected to cause phosphorylation of L-WNK1 which can also stimulate SPAK phosphorylation. L-WNK1 has other functions: a) It blocks the NCC-inhibitory form of WNK4. b) It inhibits secretion of K⁺ via ROMK channels so as to, conserve K⁺ despite high aldosterone levels. Right panel shows the pathway in the setting of high dietary K⁺ intake, when aldosterone is stimulated and angiotensin is low. In the absence of sufficient AngII, ATR1 can not activate WNK4. This reduces SPAK activation and NCC phosphorylation. At the same time, dietary potassium loading increases the KS-WNK1 isoform to suppress the activity of L-WNK1. Consequently, the full inhibitory power of WNK4 on NCC becomes unleashed, blocking traffic of NCC to the apical membrane and thereby reducing NCC surface density. KS-WNK1 also blocks the effect of L-WNK1 on ROMK endocytosis, causing ROMK to increase at the apical membrane. In this way, K⁺ secretion in the DCT and CNT/CCD is maximized while NCC is suppressed. Aldosterone stimulation of ENaC (not shown) offsets the decreased Na⁺ reabsorption by NCC, allowing robust potassium secretion without changes in sodium balance. (Not shown for clarity are WNK3, which is believed to antagonize the inhibitory effects of WNK4 on NCC; and the possible WNK4 effects on ROMK).