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Fluid and electrolyte disorders
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Ploutarchos Tzoulis, Pierre-Marc G. Bouloux
Mutations in the WNK1 gene increase the activity of the gene and lead to excess WNK1 protein expression. The excess protein abnormally increases Na reabsorption and blocks K secretion. These effects lead to increased circulating Na and K levels, causing hypertension and hyperkalemia.
Genetic Basis of Blood Pressure and Hypertension
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Sandosh Padmanabhan, Alisha Aman, Anna F. Dominiczak
Na+ reabsorption is controlled by mineralocorticoid active steroid hormones in both the distal convoluted tubule and the collecting duct (Figure 7.1). The amiloride-sensitive epithelial Na+ channel (ENaC; SCNN1A, SCNN1B, SCNN1G, SCNN1D) is found predominantly in principal cells of the collecting duct and the thiazide-sensitive sodium chloride cotransporter (NCC; SLC12A3) in the distal convoluted tubule. In addition, basolateral sodium-potassium adenosine triphosphate (ATP1A1-3, ATP1B1-4) and the luminal renal outer medulla K+ channel (ROMK; KCNJ1) are responsible for Na+ and K+ homeostasis. Aldosterone binds to the cytosolic mineralocorticoid receptor (MR; NR3C2) and leads to increased activity of the apical Na+ transporter, ENaC. Deoxycorticosterone and deoxycortisol and their metabolites are alternative agonists of the MR, with cortisol being the most important one. The 11β-hydroxysteroid dehydrogenase type 2 enzyme (HSD11B2), which converts active cortisol to the inactive cortisone, protects the MR from cortisol, an alternative agonist of the MR, thus establishing the aldosterone specificity of the MR. Additional regulatory elements that are involved include, but are not limited to, WNK (with no lysine) kinases – a family of large serine/threonine protein kinases (WNK1 and WNK4) (52). While WNK1 is widely expressed, WNK4 is expressed primarily in the kidney, localized to tight junctions. WNK4 is responsible for tonic inhibition of the thiazide-sensitive Na+ channel (SLC12A3), while WNK1 is a negative regulator of WNK4. WNK1 also activates NCC (SLC12A3), ENaC (SCNN1A, SCNN1B, SCNN1G, SCNN1D), and inhibits the renal K+ channel ROMK (KCNJ1) (52,53). Under hyperosmotic or hypotonic low-Cl− conditions, WNK isoforms are activated, and subsequently phosphorylate and activate the related protein kinases SPAK (STK39) and OSR1 (OXSR1) (54). SPAK and OSR1 phosphorylate and activate ion cotransporters that include NCC, NKCC1 (SLC12A2) and NKCC2 (SLC12A1), which are targets for the commonly thiazide-diuretic and loop-diuretic drugs, the former being an excellent antihypertensive drug (55).
Emerging drug targets for sickle cell disease: shedding light on new knowledge and advances at the molecular level
Published in Expert Opinion on Therapeutic Targets, 2023
Tyrosine kinase inhibitors, for example imatinib, to reduce band 3 phosphorylation and stabilize the cytoskeleton are also currently under clinical trials. Interestingly, however, this site also binds WNK1, a kinase inhibitor of KCl cotransport, and increased phosphorylation to displace the enzyme may therefore co-incidentally alter cotransporter activity. In addition, tyrosine kinase inhibition, in the opposite way to serine-threonine kinase inhibition, can itself lower transport activity. The exact pathways involved, their interactions, and the degree to which their modulation may be beneficial or not requires further elucidation. The many roles of band 3 in red cell physiology and pathology remain incompletely understood and represent a rich ground for future work, as evidenced by recent advances in clinical trials for malaria and SCD using tyrosine kinase inhibitors.
Lack of association of mirSNP rs11174811 in AVPR1A gene with arterial blood pressure and hypertension in South Indian population
Published in Clinical and Experimental Hypertension, 2018
Linda Koshy, S. V. Vijayalekshmi, S. Harikrishnan, Kutty V. Raman, V. T. Jissa, A. Jayakumaran Nair, A. Gangaprasad, G. M Nair, P. R. Sudhakaran
The present study was designed with sufficient power (80%) to detect a true association, albeit, with a few limitations. Firstly, stratification of the study sample based on gender could have reduced the power of the study. Secondly, a proportion of the samples who were on antihypertensive medication, could have occluded the actual BP measurements. However, we proceeded to control for the antihypertensive medication by using a censored regression model and included all participants for the analyses. Although analyzing HTN as a binary trait is a popular and valid approach, Tobin et al., 2005, suggested that this could lead to extensive loss of information in the discretization as exemplified by their analysis of the Speedwell cohort study that tested the association of APOE genotype and other traditional risk factors with an increase in SBP (19). A few other reports have also used this approach to investigate the association of other variables like renal artery calcification, major cardiovascular risk factors and WNK1 mutations with blood pressure (13,26–28).
Genetic and ethnic modulation of cardiovascular toxicity of vascular endothelial growth factor inhibitors
Published in Annals of Medicine, 2018
Yen-Chou Chen, Cheng-Chih Chung, Yung-Kuo Lin, Yi-Jen Chen
Genetic markers, such as EGLN3, EGF and WNK1, are more closely associated with bevacizumab-induced hypertension, while KDR was associated with fewer hypertensive events [75]. WNK kinases regulate sodium-chloride co-transporters in distal renal tubules [79]. Mutation of the WNK1 gene causes overexpression of co-transporters, leading to Gordon’s syndrome, a Mendelian disease with hypertension and hyperkalaemia [80]. Polymorphisms of the WNK1 gene are also associated with hypertension [81] and the treatment response to thiazide diuretics [82]. In addition, the ECF gene encodes epidermal growth factors (EGFs). It is known that the EGF receptor may increase blood pressure through influencing glomerular arterioles and sodium reabsorption in the kidneys [83]. Furthermore, both the EGLN3 and KDR genes are involved in the VEGF-A pathway. The KDR protein is a VEGF receptor. It was reported that polymorphisms of the KDR gene decrease VEGF-A’s binding ability to the KDR protein, increasing the risk of coronary artery disease [84]. EGLN3 is a member of the Egg-laying Nine (EGLN) gene family, which regulates hypoxia-inducible transcription factors (HIFs) and cellular oxygen homeostasis [85]. HIFs also increase several gene expressions related to angiogenesis, including VEGF [85]. Thus, it is reasonable that these gene markers would play certain roles in the development or prediction of bevacizumab-induced hypertension.