Multigene Kinase Network, Kidney Transport, and Salt in Essential Hypertension

Paul A Welling; Yen-Pei C Chang; Eric Delpire; James B Wade


Kidney Int. 2010;77(12):1063-1069. 

In This Article

Abstract and Introduction


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.


Hypertension (HTN) is a substantial public health problem, affecting over a billion people on the planet. It is a major independent risk factor for myocardial infarction, stroke, and end-stage renal disease. The pathogenesis of essential HTN remains unknown, but epidemiological studies point to complex genetic and environmental factors. Genes have a major role in HTN susceptibility, with the heritability of blood pressure (BP) levels estimated to be 30–35%. Major environmental triggers include obesity and diet, especially high Na+ and low K+ dietary intake. The recent discovery of Ste20-related proline–alanine-rich kinase (SPAK, also known as serine threonine kinase 39 or STK39) as a HTN susceptibility gene in the general population,[1] together with the known involvement of with-no-lysine (WNK) kinases in a rare familial disorder of HTN and hyperkalemia, now casts light on the potential importance of a multi-gene kinase network in the genesis of HTN. In fact, a flood of recent studies are beginning to shed light on the mechanisms by which dietary salt intake influences renal Na+ transport and how mutations in these kinases and ion transport genes may lead to BP dysregulation. The objective of this minireview is to highlight recent breakthroughs and to discuss areas of consensus and uncertainty in this emerging field.


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