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Sodium-bicarbonate cotransporter NBCn1 in the kidney medullary thick ascending limb cell line is upregulated under acidic conditions and enhances ammonium transport.
Lee S, Lee HJ, Yang HS, Thornell IM, Bevensee MO, Choi I
(2010) Exp Physiol 95: 926-37
MeSH Terms: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid, Ammonia, Animals, Anion Transport Proteins, Antiporters, Bicarbonates, Biological Transport, Cell Line, Chlorides, Gluconates, Hydrogen-Ion Concentration, Kidney Medulla, Kinetics, Loop of Henle, Membrane Potentials, Methylamines, Patch-Clamp Techniques, Quaternary Ammonium Compounds, Rats, SLC4A Proteins, Sodium, Sodium-Bicarbonate Symporters, Up-Regulation, Xenopus
Show Abstract · Added March 14, 2014
In this study, we examined the effect of bicarbonate transporters on ammonium/ammonia uptake in the medullary thick ascending limb cell line ST-1. Cells were treated with 1 mm ouabain and 0.2 mM bumetanide to minimize carrier-mediated NH(4)(+) transport, and the intracellular accumulation of (14)C-methylammonium/methylammonia ((14)C-MA) was determined. In CO(2)/HCO(3)(-)-free solution, cells at normal pH briefly accumulated (14)C-MA over 7 min and reached a plateau. In CO(2)/HCO(3)(-) solution, however, cells markedly accumulated (14)C-MA over the experimental period of 30 min. This CO(2)/HCO(3)(-)-dependent accumulation was reduced by the bicarbonate transporter blocker, 4,4-diisothiocyanatostilbene-2,2-disulfonate (DIDS; 0.5 mM). Replacing Cl(-) with gluconate reduced the accumulation, but the reduction was more substantial in the presence of DIDS. Incubation of cells at pH 6.8 (adjusted with NaHCO(3) in 5% CO(2)) for 24 h lowered the mean steady-state intracellular pH to 6.96, significantly lower than 7.28 for control cells. The presence of DIDS reduced (14)C-MA accumulation in control conditions but had no effect after acidic incubation. Immunoblotting showed that NBCn1 was upregulated after acidic incubation and in NH(4)Cl-containing media. The Cl(-)-HCO(3)(-) exchanger AE2 was present, but its expression remained unaffected by acidic incubation. Expressed in Xenopus oocytes, NBCn1 increased carrier-mediated (14)C-MA transport, which was abolished by replacing Na(+). Two-electrode voltage clamp of oocytes exhibited negligible current after NH(4)Cl application. These results suggest that DIDS-sensitive HCO(3)(-) extrusion normally governs NH(4)(+)/NH(3) uptake in the medullary thick ascending limb cells. We propose that, in acidic conditions, DIDS-sensitive HCO(3)(-) extrusion is inactivated, while NBCn1 is upregulated to stimulate NH(4)(+) transport.
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24 MeSH Terms
Sirt1 activation protects the mouse renal medulla from oxidative injury.
He W, Wang Y, Zhang MZ, You L, Davis LS, Fan H, Yang HC, Fogo AB, Zent R, Harris RC, Breyer MD, Hao CM
(2010) J Clin Invest 120: 1056-68
MeSH Terms: Animals, Apoptosis, Cells, Cultured, Cyclooxygenase 2, Fibrosis, Heterocyclic Compounds, 4 or More Rings, Kidney Medulla, Male, Mice, Mice, Inbred C57BL, Oxidative Stress, Resveratrol, Sirtuin 1, Stilbenes, Ureteral Obstruction
Show Abstract · Added December 10, 2013
Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase that exerts many of the pleiotropic effects of oxidative metabolism. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress. Here, we set out to investigate the role of Sirt1 in the kidney. Our initial analysis indicated that it was abundantly expressed in mouse renal medullary interstitial cells in vivo. Knocking down Sirt1 expression in primary mouse renal medullary interstitial cells substantially reduced cellular resistance to oxidative stress, while pharmacologic Sirt1 activation using either resveratrol or SRT2183 improved cell survival in response to oxidative stress. The unilateral ureteral obstruction (UUO) model of kidney injury induced markedly more renal apoptosis and fibrosis in Sirt1+/- mice than in wild-type controls, while pharmacologic Sirt1 activation substantially attenuated apoptosis and fibrosis in wild-type mice. Moreover, Sirt1 deficiency attenuated oxidative stress-induced COX2 expression in cultured mouse renal medullary interstitial cells, and Sirt1+/- mice displayed reduced UUO-induced COX2 expression in vivo. Conversely, Sirt1 activation increased renal medullary interstitial cell COX2 expression both in vitro and in vivo. Furthermore, exogenous PGE2 markedly reduced apoptosis in Sirt1-deficient renal medullary interstitial cells following oxidative stress. Taken together, these results identify Sirt1 as an important protective factor for mouse renal medullary interstitial cells following oxidative stress and suggest that the protective function of Sirt1 is partly attributable to its regulation of COX2 induction. We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress.
1 Communities
4 Members
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15 MeSH Terms
NO solution for a radical problem: a TAL story.
Gongora MC, Harrison DG
(2010) Am J Physiol Renal Physiol 298: F883-4
MeSH Terms: Humans, Kidney Medulla, Loop of Henle, Nitric Oxide, Peroxynitrous Acid, Superoxides
Added December 10, 2013
1 Communities
1 Members
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6 MeSH Terms
Intrarenal dopamine attenuates deoxycorticosterone acetate/high salt-induced blood pressure elevation in part through activation of a medullary cyclooxygenase 2 pathway.
Yao B, Harris RC, Zhang MZ
(2009) Hypertension 54: 1077-83
MeSH Terms: Analysis of Variance, Animals, Benzazepines, Blood Pressure Determination, Blotting, Western, Cyclooxygenase 2, Desoxycorticosterone, Dinoprostone, Disease Models, Animal, Dopamine, Hypertension, Immunohistochemistry, Kidney Medulla, Mice, Mice, Knockout, Probability, Random Allocation, Sodium Chloride, Dietary
Show Abstract · Added December 10, 2013
Locally produced dopamine in the renal proximal tubule inhibits salt and fluid reabsorption, and a dysfunctional intrarenal dopaminergic system has been reported in essential hypertension and experimental hypertension models. Using catechol-O-methyl-transferase knockout (COMT(-/-)) mice, which have increased renal dopamine because of deletion of the major renal dopamine-metabolizing enzyme, we investigated the effect of intrarenal dopamine on the development of hypertension in the deoxycorticosterone acetate/high-salt (DOCA/HS) model. DOCA/HS led to significant increases in systolic blood pressure in wild-type mice (from 115+/-2 to 153+/-4 mm Hg), which was significantly attenuated in COMT(-/-) mice (from 114+/-2 to 135+/-3 mm Hg). In DOCA/HS COMT(-/-) mice, the D1-like receptor antagonist SCH-23390 increased systolic blood pressure (156+/-2 mm Hg). DOCA/HS COMT(-/-) mice also exhibited more urinary sodium excretion (COMT(-/-) versus wild-type: 3038+/-430 versus 659+/-102 micromol/L per 24 hours; P<0.01). Furthermore, DOCA/HS-induced renal oxidative stress was significantly attenuated in COMT(-/-) mice. COX-2-derived prostaglandins in the renal medulla promote sodium excretion, and dopamine stimulates medullary prostaglandin production. Renal medullary COX-2 expression and urinary prostaglandin E2 excretion were significantly higher in COMT(-/-) than in wild-type mice after DOCA/HS treatment. In DOCA/HS-treated COMT(-/-) mice, the COX-2 inhibitor SC-58236 reduced urinary sodium and prostaglandin E(2) excretion and increased systolic blood pressure (153+/-2 mm Hg). These studies indicate that an activated renal dopaminergic system attenuates the development of hypertension, at least in large part through activating medullary COX-2 expression/activity, and also decreases oxidative stress resulting from DOCA/HS.
1 Communities
2 Members
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18 MeSH Terms
High-throughput screening reveals a small-molecule inhibitor of the renal outer medullary potassium channel and Kir7.1.
Lewis LM, Bhave G, Chauder BA, Banerjee S, Lornsen KA, Redha R, Fallen K, Lindsley CW, Weaver CD, Denton JS
(2009) Mol Pharmacol 76: 1094-103
MeSH Terms: Animals, Cell Line, Genetic Testing, Heterocyclic Compounds, 1-Ring, Humans, Kidney Medulla, Potassium Channel Blockers, Potassium Channels, Inwardly Rectifying, Rats, Small Molecule Libraries
Show Abstract · Added March 24, 2014
The renal outer medullary potassium channel (ROMK) is expressed in the kidney tubule and critically regulates sodium and potassium balance. The physiological functions of other inward rectifying K(+) (Kir) channels expressed in the nephron, such as Kir7.1, are less well understood in part due to the lack of selective pharmacological probes targeting inward rectifiers. In an effort to identify Kir channel probes, we performed a fluorescence-based, high-throughput screen (HTS) of 126,009 small molecules for modulators of ROMK function. Several antagonists were identified in the screen. One compound, termed VU590, inhibits ROMK with submicromolar affinity, but has no effect on Kir2.1 or Kir4.1. Low micromolar concentrations inhibit Kir7.1, making VU590 the first small-molecule inhibitor of Kir7.1. Structure-activity relationships of VU590 were defined using small-scale parallel synthesis. Electrophysiological analysis indicates that VU590 is an intracellular pore blocker. VU590 and other compounds identified by HTS will be instrumental in defining Kir channel structure, physiology, and therapeutic potential.
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10 MeSH Terms
Placental insufficiency associated with loss of Cited1 causes renal medullary dysplasia.
Sparrow DB, Boyle SC, Sams RS, Mazuruk B, Zhang L, Moeckel GW, Dunwoodie SL, de Caestecker MP
(2009) J Am Soc Nephrol 20: 777-86
MeSH Terms: Animals, Female, Fetal Growth Retardation, Gene Expression, Humans, Infant, Kidney, Kidney Diseases, Kidney Medulla, Mice, Mice, Inbred C57BL, Nuclear Proteins, Placenta, Placental Insufficiency, Pregnancy, Trans-Activators, Transcription Factors, Transcription, Genetic
Show Abstract · Added January 5, 2011
A number of studies have shown that placental insufficiency affects embryonic patterning of the kidney and leads to a decreased number of functioning nephrons in adulthood; however, there is circumstantial evidence that placental insufficiency may also affect renal medullary growth, which could account for cases of unexplained renal medullary dysplasia and for abnormalities in renal function among infants who had experienced intrauterine growth retardation. We observed that mice with late gestational placental insufficiency associated with genetic loss of Cited1 expression in the placenta had renal medullary dysplasia. This was not caused by lower urinary tract obstruction or by defects in branching of the ureteric bud during early nephrogenesis but was associated with decreased tissue oxygenation and increased apoptosis in the expanding renal medulla. Loss of placental Cited1 was required for Cited1 mutants to develop renal dysplasia, and this was not dependent on alterations in embryonic Cited1 expression. Taken together, these findings suggest that renal medullary dysplasia in Cited1 mutant mice is a direct consequence of decreased tissue oxygenation resulting from placental insufficiency.
2 Communities
1 Members
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18 MeSH Terms
Soluble HB-EGF induces epithelial-to-mesenchymal transition in inner medullary collecting duct cells by upregulating Snail-2.
Smith JP, Pozzi A, Dhawan P, Singh AB, Harris RC
(2009) Am J Physiol Renal Physiol 296: F957-65
MeSH Terms: Animals, Cadherins, Cell Dedifferentiation, Cell Line, Epithelial Cells, Gene Expression, Gene Knockdown Techniques, Heparin-binding EGF-like Growth Factor, Intercellular Signaling Peptides and Proteins, Kidney Medulla, Kidney Tubules, Collecting, Mesenchymal Stem Cells, Mice, Mice, Nude, Snail Family Transcription Factors, Solubility, Transcription Factors, Transcription, Genetic, Transforming Growth Factor beta, Up-Regulation
Show Abstract · Added February 24, 2014
Animal models of acute renal injury suggest that the epidermal growth factor receptor (EGFR) axis may have a beneficial role in the recovery from acute renal injury, but recent reports describe detrimental effects of EGFR activation in chronic renal injury. Expression of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) increases following renal injury, but the effects of this sustained upregulation have not been well studied. Here, stable overexpression of soluble HB-EGF (sHB-EGF) in mouse inner medullary collecting duct (IMCD) cells led to marked phenotypic changes: sHB-EGF-expressing cells demonstrated a fibroblast-like morphology, did not form epithelial sheets, exhibited cytoplasmic projections, decreased expression of epithelial markers, and increased expression of fibroblast-specific protein-1. They also demonstrated anchorage-independent growth and formed tumors when injected subcutaneously into nude mice. Quantitative RT-PCR and a luciferase reporter assay suggested that sHB-EGF repressed transcription of E-cadherin, and a concomitant TGF-beta-independent upregulation of the E-cadherin repressor Snail-2 was observed. Stable downregulation of Snail-2 in sHB-EGF-overexpressing cells restored epithelial characteristics (E-cadherin and cytokeratin expression) but did not alter their anchorage-independent growth. In summary, sustained exposure to sHB-EGF induces epithelial-to-mesenchymal transition of IMCD cells, in part by upregulating the E-cadherin transcriptional repressor Snail-2.
1 Communities
4 Members
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20 MeSH Terms
Inactivation of Pkd1 in principal cells causes a more severe cystic kidney disease than in intercalated cells.
Raphael KL, Strait KA, Stricklett PK, Miller RL, Nelson RD, Piontek KB, Germino GG, Kohan DE
(2009) Kidney Int 75: 626-33
MeSH Terms: Animals, Kidney Cortex, Kidney Diseases, Cystic, Kidney Medulla, Kidney Tubules, Collecting, Mice, Mice, Knockout, Mice, Transgenic, Phenotype, TRPP Cation Channels
Show Abstract · Added September 9, 2013
Renal cysts in autosomal dominant polycystic kidney disease arise from cells throughout the nephron, but there is an uncertainty as to whether both the intercalated cells (ICs) and principal cells (PCs) within the collecting duct give rise to cysts. To determine this, we crossed mice containing loxP sites within introns 1 and 4 of the Pkd1 gene with transgenic mice expressing Cre recombinase under control of the aquaporin-2 promoter or the B1 subunit of the proton ATPase promoter, thereby generating PC- or IC-specific knockout of Pkd1, respectively. Mice, that had Pkd1 deleted in the PCs, developed progressive cystic kidney disease evident during the first postnatal week and had an average lifespan of 8.2 weeks. There was no change in the cellular cAMP content or membrane aquaporin-2 expression in their kidneys. Cysts were present in the cortex and outer medulla but were absent in the papilla. Mice in which PKd1 was knocked out in the ICs had a very mild cystic phenotype as late as 13 weeks of age, limited to 1-2 cysts and confined to the outer rim of the kidney cortex. These mice lived to at least 1.5 years of age without evidence of early mortality. Our findings suggest that PCs are more important than ICs for cyst formation in polycystic kidney disease.
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10 MeSH Terms
Increased dietary NaCl induces renal medullary PGE2 production and natriuresis via the EP2 receptor.
Chen J, Zhao M, He W, Milne GL, Howard JR, Morrow J, H├ębert RL, Breyer RM, Chen J, Hao CM
(2008) Am J Physiol Renal Physiol 295: F818-25
MeSH Terms: Animals, Dinoprostone, Kidney Medulla, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Natriuresis, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP2 Subtype, Sodium, Sodium Chloride, Dietary
Show Abstract · Added December 21, 2013
A high-NaCl diet induces renal medullary cyclooxygenase (COX)2 expression, and selective intramedullary infusion of a COX2 inhibitor increases blood pressure in rats on a high-salt diet. The present study characterized the specific prostanoid contributing to the antihypertensive effect of COX2. C57BL/6J mice placed on a high-NaCl diet exhibited increased medullary COX2 and microsomal prostaglandin E synthase1 (mPGES1) expression as determined by immunoblot and real-time PCR. Cytosolic prostaglandin E synthase and prostacyclin synthase were not induced by the high-salt diet. Immunofluorescence showed mPGES1 in collecting ducts and interstitial cells. High salt increased renal medullary PGE(2) as determined by gas chromatography/negative ion chemical ionization mass spectrometry. The effect of direct intramedullary PGE(2) infusion was examined in anesthetized uninephrectomized mice. Intramedullary PGE(2) infusion (10 ng/h) increased urine volume (from 3.3 +/- 0.6 to 9.5 +/- 1.6 mul/min) and urine sodium excretion (0.11 +/- 0.02 to 0.32 +/- 0.05 mueq/min). To determine which E-prostanoid (EP) receptor(s) mediated PGE(2)- dependent natriuresis, EP-selective prostanoids were infused. The EP(2) agonist butaprost produced natriuresis (from 0.06 +/- 0.02 to 0.32 +/- 0.05 mueq/min). The natriuretic effect of intramedullary PGE(2) or butaprost was abolished in EP2-deficient mice, which exhibit NaCl-dependent hypertension. In conclusion, a high-salt diet increases renal medullary COX2 and mPGES1 expression, and increases renal medullary PGE(2) synthesis. Renal medullary PGE(2) promotes renal sodium excretion via the EP2 receptor, thereby maintaining normotension in the setting of high salt intake.
2 Communities
2 Members
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12 MeSH Terms
alpha2-Adrenergic agonists protect against radiocontrast-induced nephropathy in mice.
Billings FT, Chen SW, Kim M, Park SW, Song JH, Wang S, Herman J, D'Agati V, Lee HT
(2008) Am J Physiol Renal Physiol 295: F741-8
MeSH Terms: Adrenergic alpha-Agonists, Animals, Cell Line, Clonidine, Contrast Media, Dexmedetomidine, Iohexol, Kidney Diseases, Kidney Medulla, Male, Mice, Mice, Inbred C57BL, Renal Circulation
Show Abstract · Added January 20, 2015
Radiocontrast nephropathy (RCN) is a common clinical problem for which there is no effective therapy. Utilizing a murine model, we tested the hypothesis that alpha(2)-adrenergic receptor agonists (clonidine and dexmedetomidine) protect against RCN induced with iohexol (a nonionic low-osmolar radiocontrast). C57BL/6 mice were pretreated with saline, clonidine, or dexmedetomidine before induction of RCN. Some mice were pretreated with yohimbine (a selective alpha(2)-receptor antagonist) before saline, clonidine, or dexmedetomidine administration. alpha(2)-Agonist-treated mice had reduced plasma creatinine, renal tubular necrosis, renal apoptosis, and renal cortical proximal tubule vacuolization 24 h after iohexol injection. Yohimbine reversed the protective effects of clonidine and dexmedetomidine pretreatment. Injection of iohexol resulted in a rapid ( approximately 90 min) fall of renal outer medullary blood flow. Clonidine and dexmedetomidine pretreatment significantly attenuated this perfusion decrease without changing systemic blood pressure. To determine whether proximal tubular alpha(2)-adrenergic receptors mediate the cytoprotective effects, we treated cultured human proximal tubule (HK-2) cells and rat pulmonary microvascular endothelial cells with iohexol after vehicle, clonidine, or dexmedetomidine pretreatment. Iohexol caused a direct dose-dependent reduction of HK-2 and rat pulmonary microvascular endothelial cell viability, but alpha(2)-agonists failed to preserve the viability of both cell types. We conclude that alpha(2)-adrenergic receptor agonists protect mice against RCN by preserving outer medullary renal blood flow. As alpha(2)-agonists are widely utilized during the perioperative period, our findings may have significant clinical relevance to improving outcomes following radiocontrast exposure.
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13 MeSH Terms