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https://www.readbyqxmd.com/read/27878608/claudins-in-barrier-and-transport-function-the-kidney
#1
REVIEW
Yongfeng Gong, Jianghui Hou
Claudins are discovered to be key players in renal epithelial physiology. They are involved in developmental, physiological, and pathophysiological differentiation. In the glomerular podocytes, claudin-1 is an important determinant of cell junction fate. In the proximal tubule, claudin-2 plays important roles in paracellular salt reabsorption. In the thick ascending limb, claudin-14, -16, and -19 regulate the paracellular reabsorption of calcium and magnesium. Recessive mutations in claudin-16 or -19 cause an inherited calcium and magnesium losing disease...
November 23, 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/27798271/wnk-cab39-nkcc1-signaling-increases-the-susceptibility-to-ischemic-brain-damage-in-hypertensive-rats
#2
Mohammad Iqbal H Bhuiyan, Shanshan Song, Hui Yuan, Gulnaz Begum, Julia Kofler, Kristopher T Kahle, Sung-Sen Yang, Shih-Hua Lin, Seth L Alper, Arohan R Subramanya, Dandan Sun
With-no-lysine kinase (WNK) and Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) are involved in the pathogenesis of hypertension. In this study, we investigated the WNK-NKCC1 signaling pathway in spontaneously hypertensive rats (SHR) and their associated susceptibility to stroke injury. Basal NKCC1 protein levels were higher in SHR than in normotensive Wistar Kyoto (WKY) rat brains. After inducing ischemic stroke, adult male WKY and SHR received either saline or NKCC1 inhibitor bumetanide (10 mg/kg/day, i.p.) starting at 3-h post-reperfusion...
October 26, 2016: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/27780982/a-patient-with-pseudohypoaldosteronism-type-ii-complicated-by-congenital-hypopituitarism-carrying-a-klhl3-mutation
#3
Marie Mitani, Munehiro Furuichi, Satoshi Narumi, Tomonobu Hasegawa, Motoko Chiga, Shinichi Uchida, Seiji Sato
Pseudohypoaldosteronism type II (PHA II) is a renal tubular disease that causes hyperkalemia, hypertension, and metabolic acidosis. Mutations in four genes (WNK4, WNK1, KLHL3, and CUL3) are known to cause PHA II. We report a patient with PHA II carrying a KLHL3 mutation, who also had congenital hypopituitarism. The patient, a 3-yr-old boy, experienced loss of consciousness at age 10 mo. He exhibited growth failure, hypertension, hyperkalemia, and metabolic acidosis. We diagnosed him as having PHA II because he had low plasma renin activity with normal plasma aldosterone level and a low transtubular potassium gradient...
October 2016: Clinical Pediatric Endocrinology: Case Reports and Clinical Investigations: Official Journal of the Japanese Society for Pediatric Endocrinology
https://www.readbyqxmd.com/read/27753931/os-05-06-in-primary-aldosteronism-mineralocorticoids-and-potassium-influence-abundance-of-the-thiazide-sensitive-sodium-chloride-cotransporter
#4
Wolley Mj, Wu A, Xu S, Gordon Rd, Fenton Ra, Stowasser M
BACKGROUND: Distal tubular sodium retention is a potent driver of hypertension, with the thiazide sensitive sodium-chloride cotransporter (NCC) a key player. The upstream modulators of NCC are unclear, but recent evidence has revealed the kinases 'with-no-lysine kinase 4' (WNK4) and 'STE20/SPS1-related, proline alanine-rich kinase' (SPAK) to be involved. The wider role of mineralocorticoids is poorly understood, but animal models implicate aldosterone as a potent regulator, possibly via effects on plasma potassium...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27727489/phosphorylation-of-klhl3-at-serine-433-impairs-its-interaction-with-the-acidic-motif-of-wnk4-a-molecular-dynamics-study
#5
Lingyun Wang, Ji-Bin Peng
Interaction between the acidic motif (AM) of protein kinase WNK4 and the Kelch domain of KLHL3 are involved in the pathogenesis of pseudohypoaldosteronism type II, a hereditary form of hypertension. This interaction is disrupted by some disease-causing mutations in either WNK4 or KLHL3, or by angiotensin II- and insulin-induced phosphorylation of KLHL3 at serine 433, which is also a site frequently mutated in patients. However, the mechanism by which this phosphorylation disrupts the interaction is unclear...
October 11, 2016: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/27643324/os-05-06-in-primary-aldosteronism-mineralocorticoids-and-potassium-influence-abundance-of-the-thiazide-sensitive-sodium-chloride-cotransporter
#6
Wolley Mj, Wu A, Xu S, Gordon Rd, Fenton Ra, Stowasser M
BACKGROUND: Distal tubular sodium retention is a potent driver of hypertension, with the thiazide sensitive sodium-chloride cotransporter (NCC) a key player. The upstream modulators of NCC are unclear, but recent evidence has revealed the kinases 'with-no-lysine kinase 4' (WNK4) and 'STE20/SPS1-related, proline alanine-rich kinase' (SPAK) to be involved. The wider role of mineralocorticoids is poorly understood, but animal models implicate aldosterone as a potent regulator, possibly via effects on plasma potassium...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27622885/fgf23-klotho-signaling-axis-in-the-kidney
#7
Reinhold G Erben, Olena Andrukhova
Fibroblast growth factor-23 (FGF23) is a bone-derived hormone protecting against the potentially deleterious effects of hyperphosphatemia by suppression of phosphate reabsorption and of active vitamin D hormone synthesis in the kidney. The kidney is one of the main target organs of FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23-Klotho signaling in the kidney. During recent years, it has become clear that FGF23 acts independently on proximal and distal tubular epithelium...
September 10, 2016: Bone
https://www.readbyqxmd.com/read/27508683/-op-lb01-10-the-skipping-of-exon-9-in-cullin-3-causes-a-severe-form-of-familial-hyperkalemic-hypertension-in-mice
#8
C Rafael, W Abdel Khalek, I Kouranti, E Clauser, X Jeunemaitre, J Hadchouel
OBJECTIVE: Familial Hyperkalemic Hypertension (FHHt) is caused by mutations in WNK1, WNK4, KLHL3 or CUL3 (cullin-3). Patients with CUL3 mutation display a more severe phenotype. The mechanisms associated with this severity remain unclear. DESIGN AND METHOD: All CUL3 mutations result in the skipping of exon 9. We have generated a mouse model of "Cul3-FHHt" by deleting Cul3 exon 9. RESULTS: RT-PCR proved that the exon skipping occurred as expected in the kidney of Cul3+/d9 mice...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27381844/in-primary-aldosteronism-mineralocorticoids-influence-exosomal-sodium-chloride-cotransporter-abundance
#9
Martin J Wolley, Aihua Wu, Shengxin Xu, Richard D Gordon, Robert A Fenton, Michael Stowasser
Distal tubular sodium retention is a potent driver of hypertension, and the thiazide-sensitive sodium-chloride cotransporter (NCC) has a key role in this process. In humans, factors regulating NCC are unclear, but in animal models, aldosterone is a potent regulator, possibly via effects on plasma potassium. We studied the effects of the mineralocorticoid fludrocortisone on the abundance of NCC and its phosphorylated form (pNCC) as well as WNK lysine deficient protein kinase 4 (WNK4) and STE20/SPS1-related, proline alanine-rich kinase (SPAK) in human urinary exosomes...
July 5, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27378813/romk-expression-remains-unaltered-in-a-mouse-model-of-familial-hyperkalemic-hypertension-caused-by-the-cul3%C3%AE-403-459-mutation
#10
Meena Murthy, Thimo Kurz, Kevin M O'Shaughnessy
Familial hyperkalemic hypertension (FHHt) is a rare inherited form of salt-dependent hypertension caused by mutations in proteins that regulate the renal Na(+)-Cl(-) cotransporter NCC Mutations in four genes have been reported to cause FHHt including CUL3 (Cullin3) that encodes a component of a RING E3 ligase. Cullin-3 binds to WNK kinase-bound KLHL3 (the substrate recognition subunit of the ubiquitin ligase complex) to promote ubiquitination and proteasomal degradation of WNK kinases. Deletion of exon 9 from CUL3 (affecting residues 403-459, CUL3(Δ403-459)) causes a severe form of FHHt (PHA2E) that is recapitulated closely in a knock-in mouse model...
July 2016: Physiological Reports
https://www.readbyqxmd.com/read/27322883/the-regulation-of-na-cl-cotransporter-by-with-no-lysine-kinase-4
#11
Eduardo R Argaiz, Gerardo Gamba
PURPOSE OF REVIEW: Abundant evidence supports that the NaCl cotransporter (NCC) activity is tightly regulated by the with-no-lysine (WNK) kinases. Here, we summarize the data regarding NCC regulation by WNKs, with a particular emphasis on WNK4. RECENT FINDINGS: Several studies involving in-vivo and in-vitro models have provided paradoxical data regarding WNK4 regulation of the NCC. Although some studies show that WNK4 can activate the NCC, other equally compelling studies show that WNK4 inhibits the NCC...
September 2016: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/27314050/novel-association-of-wnk4-gene-ala589ser-polymorphism-in-essential-hypertension-and-type-2-diabetes-mellitus-in-malaysia
#12
Nooshin Ghodsian, Patimah Ismail, Salma Ahmadloo, Farzad Heidari, Polin Haghvirdizadeh, Sima Ataollahi Eshkoor, Ali Etemad
With-no-lysine (K) Kinase-4 (WNK4) consisted of unique serine and threonine protein kinases, genetically associated with an autosomal dominant form of hypertension. Argumentative consequences have lately arisen on the association of specific single nucleotide polymorphisms of WNK4 gene and essential hypertension (EHT). The aim of this study was to determine the association of Ala589Ser polymorphism of WNK4 gene with essential hypertensive patients in Malaysia. WNK4 gene polymorphism was specified utilizing mutagenically separated polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method in 320 subjects including 163 cases and 157 controls...
2016: Journal of Diabetes Research
https://www.readbyqxmd.com/read/27131446/-wnk-ing-at-death-with-no-lysine-wnk-kinases-in-neuropathies-and-neuronal-survival
#13
REVIEW
Bor Luen Tang
Members of With-no-lysine (WNK) family of serine-threonine kinase are key regulators of chloride ion transport in diverse cell types, controlling the activity and the surface expression of cation-chloride (Na(+)/K(+)-Cl(-)) co-transporters. Mutations in WNK1 and WNK4 are linked to a hereditary form of hypertension, and WNKs have been extensively investigated pertaining to their roles in renal epithelial ion homeostasis. However, some members of the WNK family and their splice isoforms are also expressed in the mammalian brain, and have been implicated in aspects of hereditary neuropathy as well as neuronal and glial survival...
July 2016: Brain Research Bulletin
https://www.readbyqxmd.com/read/27011246/-new-perspective-on-the-role-of-wnk1-and-wnk4-in-the-regulation-of%C3%A2-nacl-reabsorption-and-k-secretion-by-the-distal-nephron
#14
Chloé Rafael, Maria Chavez-Canales, Juliette Hadchouel
The study of Familial Hyperkalemic Hypertension (FHHt), a rare monogenic disease, allowed remarkable advances in the understanding of the mechanisms of regulation of NaCl reabsorption by the distal nephron. FHHt results from mutations in the genes encoding WNK1 and WNK4, two serine-threonine kinases of the WNK (With No lysine [K]) family. The clinical manifestations of FHHt are due, among others, to an increased activity of the Na(+)-Cl(-) cotransporter NCC. Several groups therefore tried to understand how WNK1 and WNK4 could regulate NCC...
March 2016: Médecine Sciences: M/S
https://www.readbyqxmd.com/read/26863326/regulation-of-renal-electrolyte-transport-by-wnk-and-spak-osr1-kinases
#15
Juliette Hadchouel, David H Ellison, Gerardo Gamba
The discovery of four genes responsible for pseudohypoaldosteronism type II, or familial hyperkalemic hypertension, which features arterial hypertension with hyperkalemia and metabolic acidosis, unmasked a complex multiprotein system that regulates electrolyte transport in the distal nephron. Two of these genes encode the serine-threonine kinases WNK1 and WNK4. The other two genes [kelch-like 3 (KLHL3) and cullin 3 (CUL3)] form a RING-type E3-ubiquitin ligase complex that modulates WNK1 and WNK4 abundance. WNKs regulate the activity of the Na(+):Cl(-) cotransporter (NCC), the epithelial sodium channel (ENaC), the renal outer medullary potassium channel (ROMK), and other transport pathways...
2016: Annual Review of Physiology
https://www.readbyqxmd.com/read/26662201/cell-specific-regulation-of-l-wnk1-by-dietary-k
#16
Tennille N Webb, Rolando Carrisoza-Gaytan, Nicolas Montalbetti, Anna Rued, Ankita Roy, Alexandra M Socovich, Arohan R Subramanya, Lisa M Satlin, Thomas R Kleyman, Marcelo D Carattino
Flow-induced K(+) secretion in the aldosterone-sensitive distal nephron is mediated by high-conductance Ca(2+)-activated K(+) (BK) channels. Familial hyperkalemic hypertension (pseudohypoaldosteronism type II) is an inherited form of hypertension with decreased K(+) secretion and increased Na(+) reabsorption. This disorder is linked to mutations in genes encoding with-no-lysine kinase 1 (WNK1), WNK4, and Kelch-like 3/Cullin 3, two components of an E3 ubiquitin ligase complex that degrades WNKs. We examined whether the full-length (or "long") form of WNK1 (L-WNK1) affected the expression of BK α-subunits in HEK cells...
January 1, 2016: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/26608788/pth-modulation-of-ncc-activity-regulates-trpv5-ca2-reabsorption
#17
Robert S Hoover, Viktor Tomilin, Lauren Hanson, Oleh Pochynyuk, Benjamin Ko
Since parathyroid hormone (PTH) is known to increase transient receptor potential vanilloid (TRPV)5 activity and decrease Na(+)-Cl(-) cotransporter (NCC) activity, we hypothesized that decreased NCC-mediated Na(+) reabsorption contributes to the enhanced TRPV5 Ca(2+) reabsorption seen with PTH. To test this, we used mDCT15 cells expressing functional TRPV5 and ruthenium red-sensitive (45)Ca(2+) uptake. PTH increased (45)Ca(2+) uptake to 8.8 ± 0.7 nmol·mg(-1)·min(-1) (n = 4, P < 0.01) and decreased NCC activity from 75...
January 15, 2016: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/26607111/degradation-by-cullin-3-and-effect-on-wnk-kinases-suggest-a-role-of-klhl2-in-the-pathogenesis-of-familial-hyperkalemic-hypertension
#18
Chong Zhang, Nicholas P Meermeier, Andrew S Terker, Katharina I Blankenstein, Jeffrey D Singer, Juliette Hadchouel, David H Ellison, Chao-Ling Yang
Mutations in WNK1 and WNK4, and in components of the Cullin-Ring Ligase system, kelch-like 3 (KLHL3) and Cullin 3 (CUL3), can cause the rare hereditary disease, Familial Hyperkalemic Hypertension (FHHt). The disease is characterized by overactivity of the renal sodium chloride cotransporter (NCC), which is phosphorylated and activated by the WNK-stimulated Ste20-type kinases, SPAK and OSR1. WNK kinases themselves can be targeted for ubiquitination and degradataion by the CUL3-KLHL3 E3 ubiquitin ligase complex...
January 1, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26490675/generation-and-analysis-of-knock-in-mice-carrying-pseudohypoaldosteronism-type-ii-causing-mutations-in-the-cullin-3-gene
#19
Yuya Araki, Tatemitsu Rai, Eisei Sohara, Takayasu Mori, Yuichi Inoue, Kiyoshi Isobe, Eriko Kikuchi, Akihito Ohta, Sei Sasaki, Shinichi Uchida
Pseudohypoaldosteronism type II (PHAII) is a hereditary hypertensive disease caused by mutations in four different genes: with-no-lysine kinases (WNK) 1 and 4, Kelch-like family member 3 (KLHL3), and cullin 3 (Cul3). Cul3 and KLHL3 form an E3 ligase complex that ubiquitinates and reduces the expression level of WNK4. PHAII-causing mutations in WNK4 and KLHL3 impair WNK4 ubiquitination. However, the molecular pathogenesis of PHAII caused by Cul3 mutations is unclear. In cultured cells and human leukocytes, PHAII-causing Cul3 mutations result in the skipping of exon 9, producing mutant Cul3 protein lacking 57 amino acids...
2015: Biology Open
https://www.readbyqxmd.com/read/26435498/impaired-degradation-of-wnk-by-akt-and-pka-phosphorylation-of-klhl3
#20
Yuki Yoshizaki, Yutaro Mori, Yoshihito Tsuzaki, Takayasu Mori, Naohiro Nomura, Mai Wakabayashi, Daiei Takahashi, Moko Zeniya, Eriko Kikuchi, Yuya Araki, Fumiaki Ando, Kiyoshi Isobe, Hidenori Nishida, Akihito Ohta, Koichiro Susa, Yuichi Inoue, Motoko Chiga, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida, Eisei Sohara
Mutations in with-no-lysine kinase (WNK) 1, WNK4, Kelch-like 3 (KLHL3), and Cullin3 result in an inherited hypertensive disease, pseudohypoaldosteronism type II. WNK activates the Na-Cl cotransporter (NCC), increasing sodium reabsorption in the kidney. Further, KLHL3, an adapter protein of Cullin3-based E3 ubiquitin ligase, has been recently found to bind to WNK, thereby degrading them. Insulin and vasopressin have been identified as powerful activators of WNK signaling. In this study, we investigated effects of Akt and PKA, key downstream substrates of insulin and vasopressin signaling, respectively, on KLHL3...
November 13, 2015: Biochemical and Biophysical Research Communications
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