WNK Kinases, Renal Ion Transport and Hypertension

Abstract

Two members of a recently discovered family of protein kinases are the cause of an inherited disease known as pseudohypoaldosteronism type II (PHAII). These patients exhibit arterial hypertension together with hyperkalemia and metabolic acidosis. This is a mirror image of Gitelman disease that is due to inactivating mutations of the SLC12A3 gene that encodes the thiazide-sensitive Na⁺:Cl^– cotransporter. The uncovered genes causing PHAII encode for serine/threonine kinases known as WNK1 and WNK4. Physiological and biochemical studies have revealed that WNK1 and WNK4 modulate the activity of several transport pathways of the aldosterone-sensitive distal nephron, thus increasing our understanding of how diverse renal ion transport proteins are coordinated to regulate normal blood pressure levels. Observations discussed in the present work place WNK1 and WNK4 as genes involved in the genesis of essential hypertension and as potential targets for the development of antihypertensive drugs.

Activation of the renal Na + :Cl − cotransporter by angiotensin II is a WNK4-dependent process

“…NCC phosphorylation (at T58) could not be detected even on a low-salt diet. The effect of WNK4 harboring PHAII-type mutations on the distal nephron ion transport systems (NCC, ENaC, ROMK, Claudins) resembles what occurs during a low-salt diet or hypovolemia (26) in which the RAAS is activated. Thus, we proposed in a previous study that AngII could be a hormonal signal involved in switching WNK4 to the functional state promoting NCC-ENaC activation, with increased ROMK inhibition stimulating volume retention without K + wasting.…”

Gitelman syndrome DD thiazide diuretics abuse

“…It is a rare inherited autosomal recessive renal disorder with decreased tubulary resorption of Na + , Cl -, Mg 2+ and K + [3][4][5][7][8][9][10][11][12][13][14][15][16][17][18]. The prevalence of GS has been reported between 1:40000 to 1:52500 [6,12,19].…”

“…GS underlies one or more genetic mutations of the NCCT gene (SLC12A3-Gen/16q13) [3][4][5][6][7]9,10,[12][13][14][16][17][18][19][20][21]. By now, more than 100 mutations of the SLC12A3 gene (associated with GS) have been identified [6,10,12,13,16,17,21].…”

“…Renal dysfunction causes blood and urine abnormalities typically characterized by hypokalemic metabolic alkalosis, salt loss, hypomagnesaemia and hypocalciuria [2][3][4][5][6][7]9,11,[13][14][15][16][17][18]20]. These abnormalities are caused by dysfunction of thiazide-sensitive NCCT in distal convoluted tubuli [2][3][4][5][6][7]9,12,13,15,16,[18][19][20][21].…”

“…These abnormalities are caused by dysfunction of thiazide-sensitive NCCT in distal convoluted tubuli [2][3][4][5][6][7]9,12,13,15,16,[18][19][20][21]. However, dysfunction in NCCT is not directly responsible for all electrolyte abnormalities.…”