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Anita T Layton, Kamel Laghmani, Volker Vallon, Aurélie Edwards
Sodium and its associated anions are the major determinant of extracellular fluid volume, and renal Na+ reabsorption plays a crucial role in long-term blood pressure control. The goal of this study was to investigate the extent to which inhibitors of transepithelial Na$^+$ transport (T$_{\rm Na}$) along the nephron alter urinary solute excretion and T$_{\rm Na}$ efficiency, and how those effects may vary along different nephron segments. We used the multi-nephron model developed in the companion study [28], which represents detailed transcellular and paracellular transport processes along the nephrons of a rat kidney...
October 5, 2016: American Journal of Physiology. Renal Physiology
Y Zheng, L Qiu, L Fan, C Song, S Meng, J Chen
In the present study, GIFT tilapia Oreochromis niloticus were exposed to polychlorinated biphenyls (PCBs) for 7, 14, and 21 days. Over the duration of the exposure, genotoxicity and the activity of Na(+)/K(+)-ATPase (NKA) and Ca(+)/Mg(+)-ATPase (CMA) were measured in the gill, kidney, and intestine, to evaluate changes in osmoregulatory response in O. niloticus. Our results showed significant decreases in organic NKA (except in gill tissues after 0.5 mg/L PCB-exposure) and CMA activity. The results of the genotoxicity assay showed significant increases in atp1a1a, nkcc2 (only in gill tissue), and fxyd7 (except after 21 days of 5 mg/L PCB exposure)...
September 2, 2016: Genetics and Molecular Research: GMR
Christin Boldt, Tom Roeschel, Nina Himmerkus, Allein Plain, Markus Bleich, Robert Labes, Maximilian Blum, Hans Krause, Ahmed Magheli, Torsten Giesecke, Kerim Mutig, Michael Rothe, Steven M Weldon, Duska Dragun, Wolf-Hagen Schunck, Sebastian Bachmann, Alexander Paliege
Activation of the thick ascending limb (TAL) Na+-K+-2Cl--cotransporter (NKCC2) by the antidiuretic hormone arginine-vasopressin (AVP) is an essential mechanism of renal urine concentration and contributes to extracellular fluid and electrolyte homeostasis. AVP effects in the kidney are modulated by locally and/or by systemically produced epoxyeicosatrienoic acid derivates (EET). The relation between AVP and EET metabolism has not been determined. Here we show that chronic treatment of AVP-deficient Brattleboro rats with the AVP V2 receptor analog desmopressin (dDAVP; 5ng/h, 3d) significantly lowered renal EET levels (-56 ± 3% for 5,6-EET, -50 ± 3...
September 28, 2016: American Journal of Physiology. Renal Physiology
Paulo S Caceres, Mariela Mendez, Mohammed Z Haque, Pablo A Ortiz
Renal cells of the thick ascending limb (TAL) reabsorb NaCl via the apical Na(+)/K(+)/2Cl(-) co-transporter NKCC2. Trafficking of NKCC2 to the apical surface regulates NKCC2-mediated NaCl absorption and blood pressure. The molecular mechanisms by which NKCC2 reaches the apical surface and their role in renal function and maintenance of blood pressure are poorly characterized. Here we report that NKCC2 interacts with the vesicle fusion protein VAMP3, and they co-localize at the TAL apical surface. We observed that silencing VAMP3 in vivo blocks constitutive NKCC2 exocytic delivery, decreasing the amount of NKCC2 at the TAL apical surface...
October 14, 2016: Journal of Biological Chemistry
Yiyun Lou, Fan Zhang, Yuqin Luo, Liya Wang, Shisi Huang, Fan Jin
The ubiquitously expressed serum and glucocorticoid regulated kinase 1 (SGK1) is tightly regulated by osmotic and hormonal signals, including glucocorticoids and mineralocorticoids. Recently, SGK1 has been implicated as a signal hub for the regulation of sodium transport. SGK1 modulates the activities of multiple ion channels and carriers, such as epithelial sodium channel (ENaC), voltage-gated sodium channel (Nav1.5), sodium hydrogen exchangers 1 and 3 (NHE1 and NHE3), sodium-chloride symporter (NCC), and sodium-potassium-chloride cotransporter 2 (NKCC2); as well as the sodium-potassium adenosine triphosphatase (Na⁺/K⁺-ATPase) and type A natriuretic peptide receptor (NPR-A)...
2016: International Journal of Molecular Sciences
L Graham, D Graham, M W McBride, A F Dominiczak, S Padmanabhan
OBJECTIVE: UMOD-/- mice have low blood pressure and decreased salt-sensitivity indicating interactions between UMOD and sodium transport in the TAL. However, it's unclear whether the effect of UMOD is solely through interaction with cognate molecules in the TAL or whether the perturbations in physiology are more complex with involvement of both TAL and other parts of the nephron. We propose to answer this by profiling mRNA expression levels of the main ion transporters and signalling molecules in tubules from UMOD+/+ and UMOD-/- mice...
September 2016: Journal of Hypertension
B Ponte, M Pruijm, I Guessous, D Ackermann, G Ehret, M Mohaupt, F Paccaud, B Vogt, P Y Martin, A Pechere-Berstschi, M Burnier, O Devuyst, M Bochud
OBJECTIVE: Genome wide association studies have shown that the gene encoding for uromodulin (UMOD) is associated with hypertension. Recently, animal studies have demonstrated that UMOD modulates NaCl reabsorption driven by NKCC2. We hypothesised that the NaCl effect on blood pressure may be modulated by UMOD levels in the general population. DESIGN AND METHOD: Urinary UMOD levels were measured in 994 participants of the SKIPOGH population-based study who completed 24 h blood pressure monitoring and 24 h urinary collection...
September 2016: Journal of Hypertension
Orhan Efe, Janet D Klein, Lauren M LaRocque, Huiwen Ren, Jeff M Sands
Urine concentration is regulated by vasopressin. Congenital nephrogenic diabetes insipidus (NDI) is caused by vasopressin type 2 receptor (V2R) mutations. We studied whether metformin could improve urine concentration in rodent models of congenital NDI by stimulating AMPK. To block the V2R in rats, tolvaptan (10 mg/kg/d) was given by oral gavage with or without metformin (800 mg/ kg/d). Control rats received vehicle with or without metformin. Tamoxifen-induced V2R KO mice were given metformin (600 mg/kg) or vehicle twice daily...
July 21, 2016: JCI Insight
Shoujin Hao, AnnMarie DelliPizzi, Mariana Quiroz-Munoz, Houli Jiang, Nicholas R Ferreri
The mechanisms by which prostanoids contribute to the maintenance of whole body water homeostasis are complex and not fully understood. The present study demonstrates that an EP3-dependent feedback mechanism contributes to the regulation of water homeostasis under high-salt conditions. Rats on a normal diet and tap water were placed in metabolic cages and given either sulprostone (20 μg·kg(-1)·day(-1)) or vehicle for 3 days to activate EP3 receptors in the thick ascending limb (TAL). Treatment was continued for another 3 days in rats given either 1% NaCl in the drinking water or tap water...
October 1, 2016: American Journal of Physiology. Renal Physiology
Tengis S Pavlov, Vladislav Levchenko, Daria V Ilatovskaya, Carol Moreno, Alexander Staruschenko
OBJECTIVE: The Dahl salt-sensitive rat is a well-established model of salt-sensitive hypertension. The goal of this study was to assess the expression and activity of renal sodium channels and transporters in the renin-deficient salt-sensitive rat. METHODS: Renin knockout (Ren(-/-)) rats created on the salt-sensitive rat background were used to investigate the role of renin in the regulation of ion transport in salt-sensitive hypertension. Western blotting and patch-clamp analyses were utilized to assess the expression level and activity of Na(+) transporters...
July 2016: Journal of the Renin-angiotensin-aldosterone System: JRAAS
Manoocher Soleimani, Sharon Barone, Jie Xu, Saeed Alshahrani, Marybeth Brooks, Francis X McCormack, Roger D Smith, Kamyar Zahedi
Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion...
2016: PloS One
Lei Yang, Gustavo Frindt, Florian Lang, Dietmar Kuhl, Volker Vallon, Lawrence G Palmer
We examined renal Na and K transporters in mice with deletions in the gene encoding the aldosterone-induced protein SGK1. The knockout mice were hyperkalemic, and had altered expression of the subunits of the epithelial Na channel (ENaC). The kidneys showed decreased expression of the cleaved forms of the γENaC subunit, and the fully glycosylated form of the βENaC subunits when animals were fed a high-K diet. Knockout animals treated with exogenous aldosterone also had reduced subunit processing and diminished surface expression of βENaC and γENaC...
July 13, 2016: American Journal of Physiology. Renal Physiology
Yibo Zhuang, Zhanjun Jia, Caiyu Hu, Guixia Ding, Xintong Zhang, Yue Zhang, Guangrui Yang, Rajeev Rohatgi, Songming Huang, John Ci-Jiang He, Aihua Zhang
Renal resistance to loop diuretics is a frequent complication in a number of kidney disease patients with elusive mechanism. Employing human renal biopsy specimens, albumin overload mouse model, and primary cultures of mouse renal tubular cells, albuminuria effect on NKCC2 expression and function and the underlying mechanisms were investigated. In the renal biopsy specimens of albuminuric patients, we found that NKCC2 was significantly downregulated with a negative correlation with albuminuria severity as examined by immunohistochemistry...
June 23, 2016: Oncotarget
Kerim Mutig, Tordis Borowski, Christin Boldt, Aljona Borschewski, Alexander Paliege, Elena Popova, Michael Bader, Sebastian Bachmann
The antidiuretic hormone vasopressin (AVP) regulates renal salt and water reabsorption along the distal nephron and collecting duct system. These effects are mediated by vasopressin 2 receptors (V2R) and release of intracellular Gs-mediated cAMP to activate epithelial transport proteins. Inactivating mutations in the V2R gene lead to the X-linked form of nephrogenic diabetes insipidus (NDI), which has chiefly been related with impaired aquaporin 2-mediated water reabsorption in the collecting ducts. Previous work also suggested the AVP-V2R-mediated activation of Na(+)-K(+)-2Cl(-)-cotransporters (NKCC2) along the thick ascending limb (TAL) in the context of urine concentration, but its individual contribution to NDI or, more generally, to overall renal function was unclear...
August 1, 2016: American Journal of Physiology. Renal Physiology
Andrea Gerbino, Giorgia Schena, Serena Milano, Luigi Milella, Alan Franco Barbosa, Francesca Armentano, Giuseppe Procino, Maria Svelto, Monica Carmosino
Acmella oleracea is well recognized in Brazilian traditional medicine as diuretic, although few scientific data have been published to support this effect. Aim of this study was to determine the molecular effect of Acmella oleracea extract and its main alkylamide spilanthol on two major processes involved in the urine concentrating mechanism: Na-K-2Cl symporter (NKCC2) activity in the thick ascending limb and water channel aquaporin 2 accumulation at the apical plasma membrane of collecting duct cells. Phosphorylation of NKCC2 was evaluated as index of its activation by Western blotting...
2016: PloS One
Nine V A M Knoers, René J Bindels
No abstract text is available yet for this article.
May 12, 2016: New England Journal of Medicine
Kamel Laghmani, Bodo B Beck, Sung-Sen Yang, Elie Seaayfan, Andrea Wenzel, Björn Reusch, Helga Vitzthum, Dario Priem, Sylvie Demaretz, Klasien Bergmann, Leonie K Duin, Heike Göbel, Christoph Mache, Holger Thiele, Malte P Bartram, Carlos Dombret, Janine Altmüller, Peter Nürnberg, Thomas Benzing, Elena Levtchenko, Hannsjörg W Seyberth, Günter Klaus, Gökhan Yigit, Shih-Hua Lin, Albert Timmer, Tom J de Koning, Sicco A Scherjon, Karl P Schlingmann, Mathieu J M Bertrand, Markus M Rinschen, Olivier de Backer, Martin Konrad, Martin Kömhoff
BACKGROUND: Three pregnancies with male offspring in one family were complicated by severe polyhydramnios and prematurity. One fetus died; the other two had transient massive salt-wasting and polyuria reminiscent of antenatal Bartter's syndrome. METHODS: To uncover the molecular cause of this possibly X-linked disease, we performed whole-exome sequencing of DNA from two members of the index family and targeted gene analysis of other members of this family and of six additional families with affected male fetuses...
May 12, 2016: New England Journal of Medicine
Silvana Bazúa-Valenti, María Castañeda-Bueno, Gerardo Gamba
The solute carrier family 12, as numbered according to Human Genome Organisation (HUGO) nomenclature, encodes the electroneutral cation-coupled chloride cotransporters that are expressed in many cells and tissues; they play key roles in important physiological events, such as cell volume regulation, modulation of the intracellular chloride concentration, and transepithelial ion transport. Most of these family members are expressed in specific regions of the nephron. The Na-K-2Cl cotransporter NKCC2, which is located in the thick ascending limb, and the Na-Cl cotransporter, which is located in the distal convoluted tubule, play important roles in salt reabsorption and serve as the receptors for loop and thiazide diuretics, respectively (Thiazide diuretics are among the most commonly prescribed drugs in the world...
July 1, 2016: American Journal of Physiology. Renal Physiology
Kasper Lykke, Kathrin Töllner, Peter W Feit, Thomas Erker, Nanna MacAulay, Wolfgang Löscher
The Na(+)-K(+)-Cl(-) cotransporter NKCC1 plays a major role in the regulation of intraneuronal Cl(-) concentration. Abnormal functionality of NKCC1 has been implicated in several brain disorders, including epilepsy. Bumetanide is the only available selective NKCC1 inhibitor, but also inhibits NKCC2, which can cause severe adverse effects during treatment of brain disorders. A NKCC1-selective bumetanide derivative would therefore be a desirable option. In the present study, we used the Xenopus oocyte heterologous expression system to compare the effects of bumetanide and several derivatives on the two major human splice variants of NKCCs, hNKCC1A and hNKCC2A...
June 2016: Epilepsy & Behavior: E&B
Mohammed Z Ferdaus, Karl W Barber, Karen I López-Cayuqueo, Andrew S Terker, Eduardo R Argaiz, Brandon M Gassaway, Régine Chambrey, Gerardo Gamba, Jesse Rinehart, James A McCormick
KEY POINTS: STE20 (Sterile 20)/SPS-1 related proline/alanine-rich kinase (SPAK) and oxidative stress-response kinase-1 (OSR1) phosphorylate and activate the renal Na(+) -K(+) -2Cl(-) cotransporter 2 (NKCC2) and Na(+) Cl(-) cotransporter (NCC). Mouse models suggest that OSR1 mainly activates NKCC2-mediated sodium transport along the thick ascending limb, while SPAK mainly activates NCC along the distal convoluted tubule, but the kinases may compensate for each other. We hypothesized that disruption of both kinases would lead to polyuria and severe salt-wasting, and generated SPAK/OSR1 double knockout mice to test this...
September 1, 2016: Journal of Physiology
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