WNK4

Oral poisoning can trigger diverse physiological reactions, determined by the toxic substance involved. One such consequence is hyperchloremia, characterized by an elevated level of chloride in the blood and leads to kidney damage and impairing chloride ion regulation. Here, we conducted a comprehensive genome-wide analysis to investigate genes or proteins linked to hyperchloremia. Our analysis included functional enrichment, protein-protein interactions, gene expression, exploration of molecular pathways, and the identification of potential shared genetic factors contributing to the development of hyperchloremia...

UNLABELLED: Renal tubules are featured with copious mitochondria and robust transport activity. Mutations in mitochondrial genes cause congenital renal tubulopathies, and changes in transport activity affect mitochondrial morphology, suggesting mitochondrial function and transport activity are tightly coupled. Current methods of using bulk kidney tissues or cultured cells to study mitochondrial bioenergetics are limited. Here, we optimized an extracellular flux analysis (EFA) to study mitochondrial respiration and energy metabolism using microdissected mouse renal tubule segments...

Vasopressin regulates water homeostasis via the V2 receptor in the kidney at least in part through protein kinase A (PKA) activation. Vasopressin, through an unknown pathway, upregulates the activity and phosphorylation of the Na+-Cl- cotransporter (NCC) and Na+-K+-2Cl- cotransporter 2 (NKCC2) by Ste20-related Proline/Alanine rich Kinase (SPAK) and Oxidative Stress Responsive kinase 1 (OSR1), which are regulated by the With No Lysine (K) kinase (WNK) family. Phosphorylation of WNK4 at PKA consensus motifs may be involved...

In the renal collecting ducts, chloride reabsorption occurs through both transcellular and paracellular pathways. Recent literature highlights a functional interplay between both pathways. We recently showed that in polarized inner medullary collecting duct cells, expression of the basolateral kidney anion exchanger 1 (kAE1) results in a decreased transepithelial electrical resistance (TEER), in a claudin-4 dependent pathway. Claudin-4 is a paracellular sodium blocker and chloride pore. Here, we show that kAE1 expression in mouse inner medullary collecting duct cells triggers WNK4, SPAK and claudin-4 phosphorylation...

PURPOSE OF REVIEW: Hypertension, commonly known as high blood pressure, is a widespread health condition affecting a large number of individuals across the globe. Although lifestyle choices and environmental factors are known to have a significant impact on its development, there is growing recognition of the influence of genetic factors in the pathogenesis of hypertension. This review specifically focuses on the hereditary causes of hypertension that are associated with increased sodium transport through the thiazide-sensitive NaCl cotransporter (NCC) or amiloride-sensitive epithelial sodium channel (ENaC), crucial mechanisms involved in regulating blood pressure in the kidneys...

(1) Background: Gordon syndrome (GS) or familial hyperkalemic hypertension is caused by pathogenic variants in the genes WNK1 , WNK4 , KLHL3, and CUL3 . Patients presented with hypertension, hyperkalemia despite average glomerular filtration rate, hyperchloremic metabolic acidosis, and suppressed plasma renin (PR) activity with normal plasma aldosterone (PA) and sometimes failure to thrive. GS is a heterogeneous genetic syndrome, ranging from severe cases in childhood to mild and sometimes asymptomatic cases in mid-adulthood...

Genome-wide scans performed in affected sib pairs have revealed small and often inconsistent clues to the loci responsible for the inherited components of hypertension. Since blood pressure is a quantitative trait regulated by many loci, two siblings at opposite extremes of the blood pressure distribution are more likely to have inherited different alleles at any given locus. Hence, we investigated an extreme discordant sib pair strategy to analyse markers from two previous loci of interest: (1) the Gordons syndrome locus that includes the WNK4 gene and (2) the ROMK locus identified in our first genome-wide scan...

The WNK4-SPAK/OSR1 pathway mediates activating phosphorylation of the furosemide-sensitive Na+ -K+ -2Cl- cotransporter (NKCC2) and the thiazide-sensitive NaCl cotransporter (NCC). The commonly used pT96/pT101-pNKCC2 antibody cross-reacts with pT53-NCC in mice on the C57BL/6 background due to a five amino acid deletion. We generated a new C57BL/6-specific pNKCC2 antibody (anti-pT96-NKCC2) and tested the hypothesis that the WNK4-SPAK/OSR1 pathway strongly regulates phosphorylation of NCC but not NKCC2. In C57BL/6 mice, anti-pT96-NKCC2 detected pNKCC2 and did not cross-react with NCC...

UNLABELLED: Abstract: Introduction: Familial Hyperkalemic Hypertension (FHHt) is an inherited disease characterized by hyperkalemia, hypertension and hyperchloremic acidosis. The primary defect is a hyperactive sodium chloride co-transporter, expressed in the renal distal tubule (DCT). FHHt is caused by mutation in either, WNK1, WNK4, KLHL3 or Cul3. The mechanism of hyperchloremic acidosis is not completely understood. METHODS: Clinical and genetic data were collected from the largest family with FHHt described in the literature...

The primary structure of the thiazide-sensitive NaCl cotransporter (NCC) was resolved 30 years ago by the molecular identification of the cDNA encoding this cotransporter, from the winter's flounder urinary bladder, following a functional expression strategy. This review outlines some aspects of how the knowledge about thiazide diuretics and NCC evolved, the history of the cloning process, and the expansion of the SLC12 family of electroneutral cotransporters. The diseases associated with activation or inactivation of NCC are discussed, as well as the molecular model by which the activity of NCC is regulated...

PURPOSE OF REVIEW: Regulation of the sodium chloride cotransporter (NCC) in the distal convoluted tubule (DCT) plays a crucial role in renal salt handling. The calcium-sensing receptor (CaSR) has been shown to activate NCC through the WNK4-SPAK pathway, which is independent of the Renin-Angiotensin-Aldosterone system. In this review, we examine new information about the mechanism of how the CaSR regulates NCC through the WNK4-SPAK pathway and its physiological and therapeutic implications...

BACKGROUND: Studies reported that kelch-like protein 3 (KLHL3)-Cullin3(CUL3) E3 ligase ubiquitinated with-no-lysine kinase 4 (WNK4). Impaired WNK4 ubiquitination plays a key role in Familial hyperkalemic hypertension (FHHt, also called pseudohypoaldosteronism type II) which results from overaction of thiazide-sensitive sodium chloride cotransport (NCC). In addition, researchers have also found that dietary potassium deficiency activates NCC along the renal distal convoluted tubule (DCT)...

Mutations in with-no-lysine [K] kinase 4 (WNK4) and kelch-like 3 (KLHL3) are linked to pseudohypoaldosteronism type 2 (PHAII, also known as familial hyperkalemic hypertension or Gordon's syndrome). WNK4 is degraded by a ubiquitin E3 ligase with KLHL3 as the substrate adaptor for WNK4. Several PHAII-causing mutations, e.g. those in the acidic motif (AM) of WNK4 and in the Kelch domain of KLHL3, impair the binding between WNK4 and KLHL3. This results in a reduction in WNK4 degradation and an increase in WNK4 activity, leading to PHAII...

Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the acid-base balance in PHA2...

Inclement weather conditions, especially cold stress, have threatened the cattle industry. Cattle exposed to cold environments for a longer time suffer developmental delay, immunity decline, and eventually death. WNK1 is a member of With-no-lysine kinases ( WNK s), widely expressed in animal organs and tissues. WNK1 and WNK4 are expressed in adipose tissue, and WNK4 promotes adipogenesis. WNK1 does not directly affect adipogenesis but has been shown to promote WNK4 expression in several tissues or organs. One missense mutation NC_037346...

The activity of the Na+ -Cl- cotransporter (NCC) in the distal convoluted tubule (DCT) is finely tuned by phosphorylation networks involving serine/threonine kinases and phosphatases. While much attention has been paid to the With-No-lysine (K) kinase (WNK)- STE20-related Proline Alanine rich Kinase (SPAK)/Oxidative Stress Responsive kinase 1 (OSR1) signaling pathway, there remain many unanswered questions regarding phosphatase-mediated modulation of NCC and its interactors. The phosphatases shown to regulate NCC's activity, directly or indirectly, are protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A), calcineurin (CN), and protein phosphatase 4 (PP4)...

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a highly conserved cell protective protein. In this study, we explored its functions in shrimp hemocytes. Our results indicated that LvMANF knockdown could cause a decrease in total hemocyte count (THC) and an increase in caspase3/7 activity. To further explore its working mechanism, transcriptomic analyses were performed with wild-type and LvMANF-knockdown hemocytes. Three upregulated genes from transcriptomic data, including FAS-associated factor 2, rho-associated protein kinase 1, and serine/threonine-protein kinase WNK4 were validated with qPCR...

BACKGROUND: Deep learning techniques are gaining momentum in medical research. Colorectal adenoma (CRA) is a precancerous lesion that may develop into colorectal cancer (CRC) and its etiology and pathogenesis are unclear. This study aims to identify transcriptome differences between CRA and CRC via deep learning on Gene Expression Omnibus (GEO) databases and bioinformatics in the Chinese population. METHODS: In this study, three microarray datasets from the GEO database were used to identify the differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) in CRA and CRC...

Distal convoluted tubules (DCT), which contain the Na-Cl cotransporter (NCC) inhibited by thiazide diuretics, undergo complex modulation to preserve Na+ and K+ homeostasis. The lysine kinases 1 and 4 (WNK1 and WNK4), identified as hyperactive in the hereditary disease pseudohypoaldosteronism type 2, are responsible for activation of NCC and consequent hypokalemia and hypertension. WNK4, highly expressed in DCT, activates the SPAK/OSR1 kinases, which phosphorylate NCC and other regulatory proteins and transporters in the distal nephron...

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