Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The WNK kinases are a small group of serine/threonine kinases with unique catalytic domains that lack the lysine residue used in other kinases to co-ordinate ATP (hence, With No K [WNK]). Their closest homologues are found within the mitogen-activated protein kinase (MAPK) pathway suggesting a role in signalling. Two WNK isoforms, WNK1 and WNK4, have been identified as the disease genes for a rare monogenic hypertension syndrome (Gordon's syndrome or pseudohypoaldosteronism type 2 [PHA2]) implicating them in salt homeostasis by the kidney. This is supported by recent data showing widespread expression of WNK1 and WNK4 in mammalian transporting epithelia. Within the kidney, WNKs probably regulate the surface expression of several proteins involved in ion transport, including the sodium-chloride cotransporter (NCCT) and the potassium channel renal outer medullary potassium channel (ROMK), based on co-expression studies in Xenopus oocytes. WNKs, especially WNK4, have been suggested as candidate genes for essential hypertension itself, but evidence for this is lacking. Some of the effects of the WNKs are independent of their kinase function, suggesting that they are dependent on specific protein-protein interactions. It seems likely that the WNKs are part of much larger protein scaffolds in cells and have effects in cells beyond ion transport. However, because of their effect on expression of the NCCT they are attractive drug targets for the development of novel antihypertensive agents. These agents could potentially offer the efficacy of a thiazide diuretic, but without the metabolic side effects usually seen with this class of antihypertensive therapy.
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PMID:WNK kinases and the control of blood pressure. 1586 21

Several monogenic hypertensive disorders are caused by genetic mutations leading to the deranged function and/or regulation of renal tubular NaCl transport, such as mutations of the renal epithelial Na+ channel (ENaC) in Liddle syndrome, of the kinase WNK1 (with no K) in Gordon syndrome, and of the mineralocorticoid receptor, or of 11beta-hydroxysteroid dehydrogenase. Moreover, excessive formation of aldosterone in glucocorticoid-remediable hypertension leads to severe hypertension. Conversely, impaired function of the Na+,K+,2Cl- cotransporter (NKCC2), the renal outer medullary K+ channel (ROMK1), and the renal epithelial Cl- channel ClCKb/Barttin causes Bartter syndrome and defective Na+,Cl+ cotransporter (NCCT) Gitelman syndrome, salt-wasting disorders with hypotension. These monogenic disorders are rare, but illustrate the significance of renal tubular transport in blood pressure regulation. There is little doubt, however, that deranged renal salt reabsorption significantly contributes to essential hypertension polymorphisms of several genes participating in the regulation of renal Na+ transport have been shown to be associated with blood pressure and prevalence of hypertension. Two common genes will be discussed in more detail. The first encodes the renal Cl- channel ClCKb. A gain-of-function mutation of ClCKb, increasing channel activity by 7- to 20-fold is found in approximately 20% of unselected Caucasians and 40% of an unselected African population. The second common gene variant (prevalence, 3%-5% in unselected Caucasians), to be discussed in more detail, affects the serum and glucocorticoid inducible kinase SGK1, a kinase upregulated by mineralocorticoids and enhancing the activity of ENaC, ROMK, and Na+/K+ATPase. Both gene variants are associated with slightly increased blood pressure. SGK1 further stimulates the glucose transporter SGLT1, and the SGK1 gene variant correlates, in addition, with increased body mass index.
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PMID:Renal tubular transport and the genetic basis of hypertensive disease. 1598 Sep 41

Serum- and glucocorticoid-inducible kinase 1 (SGK1) is expressed following cell stress and exposure to a variety of hormones including glucocorticoids and mineralocorticoids. It is activated by insulin and growth factors via phosphatidylinositol-3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGK1 enhances the activity of a variety of ion channels such as ENaC, TRPV5, ROMK, KCNE1/KCNQ1 and ClCKb; carriers such as NHE3, NKCC2, NCC and SGLT1; as well as the Na+/K+-ATPase. SGK1 contributes to Na+ retention and K+ elimination of the kidney as well as mineralocorticoid stimulation of salt appetite. A certain SGK1 gene variant (combined polymorphisms in intron 6 [I6CC] and in exon 8 [E8CC/CT]) is associated with moderately enhanced blood pressure. The SGK1 gene variant has been shown to affect 3%-5% of whites and some 10% of Africans. The gene variant sensitizes the carriers to the hypertensive effects of hyperinsulinemia. Moreover, the SGK1 gene variant is associated with increased body mass index, presumably a result of enhanced SGLT1 activity with accelerated intestinal glucose absorption. Obesity predisposes the carriers of the gene variant to development of type 2 diabetes. Moreover, SGK1 stimulates coagulation. Thus, SGK1 may participate in the pathogenesis of metabolic syndrome or syndrome X, a condition characterized by the coincidence of essential hypertension, procoagulant state, obesity, insulin resistance and hyperinsulinemia.
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PMID:SGK, renal function and hypertension. 2117 Aug 69