WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension

Abstract

Hypertension is the most prevalent health condition worldwide, affecting ~1 billion people. Gordon's syndrome is a form of secondary hypertension that can arise due to a number of possible mutations in key genes that encode proteins in a pathway containing the With No Lysine [K] (WNK) and its downstream target kinases, SPS/Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress responsive kinase 1 (OSR1). This pathway regulates the activity of the thiazide-sensitive sodium chloride cotransporter (NCC), which is responsible for NaCl reabsorption in the distal nephron. Therefore, mutations in genes encoding proteins that regulate the NCC proteins disrupt ion homeostasis and cause hypertension by increasing NaCl reabsorption. Thiazide diuretics are currently the main treatment option for Gordon's syndrome. However, they have a number of side effects, and chronic usage can lead to compensatory adaptations in the nephron that counteract their action. Therefore, recent research has focused on developing novel inhibitory molecules that inhibit components of the WNK-SPAK/OSR1-NCC pathway, thereby reducing NaCl reabsorption and restoring normal blood pressure. In this review we provide an overview of the currently reported molecular inhibitors of the WNK-SPAK/OSR1-NCC pathway and discuss their potential as treatment options for Gordon's syndrome.

An update regarding the role of WNK kinases in cancer

“…WNKs play a key role in maintaining ion homeostasis, and their dysregulation can lead to diseases such as hypertension [ 135 ]. In recent years, more and more studies have found that WNKs are overexpressed or downregulated in cancer tissues, contributing to tumor growth, metastasis and angiogenesis.…”

The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis

“…Aberrant renal SGK1/WNK-SPAK/OSR1 regulation is involved in disease conditions such as Gordon’s Syndrome and Gitelman-like conditions [ 7 , 8 , 9 , 10 ]. Upstream kinases of the WNK-SPAK/OSR1 axis, such as SGK1 (Serum/Glucocorticoid Regulated Kinase 1) and protein kinase B (also known as AKT), both phosphorylate WNK kinases and therefore stimulate SPAK/OSR1 to activate renal ion channels including: NKCC2, NCC, ENaC, and ROMK [ 11 ].…”

The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities

“…Importantly, the inhibition/stimulation of KCC2/NKCC1 pair via protein phosphorylation is through a regulatory mechanism that works in a reciprocal pattern [53,64] and members of the with-no-lysine kinase (WNKs) family as well as their downstream targets; STE20/SPS1-related proline/alanine rich kinase (SPAK) and oxidative stress response kinase (OSR1) are the most prominent kinases that regulate this process [52,[64][65][66][67]. Consequently, impaired ion homeostasis resulting from mutation in the physiological function of some of this transporter pair and/or their upstream regulators may be detrimental and subsequently result in diminished inhibition and augmented network hyperexcitability, which underlies numerous neurological disorders [52,66,[68][69][70][71] including HD [58][59][60].…”

“…When [Cl − ] i exceeds equilibrium, depolarisation events contribute to the onset of neurological disease [35,46]. Decreased KCC2 expression coupled with increased NKCC1 expression and/or activity has been documented in several pathologies [63,68,69,71], including HD [58][59][60]. In HD, HTT is mutated (mHTT) and acts to alter KCC2 and NKCC1 expressions and activity [58,59] through mechanisms that remain undetermined.…”