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RAGE-aptamer attenuates deoxycorticosterone acetate/salt-induced renal injury in mice.
Taguchi K, Yamagishi SI, Yokoro M, Ito S, Kodama G, Kaida Y, Nakayama Y, Ando R, Yamada-Obara N, Asanuma K, Matsui T, Higashimoto Y, Brooks CR, Ueda S, Okuda S, Fukami K
(2018) Sci Rep 8: 2686
MeSH Terms: Acetates, Acute Kidney Injury, Aldosterone, Animals, Aptamers, Peptide, Blood Pressure, Desoxycorticosterone Acetate, Glycation End Products, Advanced, Hypertension, Kidney Diseases, Kidney Glomerulus, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor for Advanced Glycation End Products, Receptors, Mineralocorticoid, Sodium Chloride, Dietary
Show Abstract · Added March 14, 2019
The mineralocorticoid receptor (MR) and its downstream signaling play an important role in hypertensive renal injury. The interaction of advanced glycation end products (AGE) with their receptor (RAGE) is involved in the progression of renal disease. However, the pathological crosstalk between AGE-RAGE axis and MR system in kidney derangement remains unclear. We screened DNA-aptamer directed against RAGE (RAGE-apt) in vitro and examined its effects on renal injury in uninephrectomized deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mice. RAGE, GTP-bound Rac-1 (Rac1), and MR were co-localized in the podocytes of DOCA mice. The deletion of RAGE gene significantly inhibited mesangial matrix expansion and tubulointerstitial fibrosis in DOCA mice, which was associated with the reduction of glomerular oxidative stress, MR, Rac1, and urinary albumin excretion (UAE) levels. RAGE-apt attenuated the increase in carboxymethyllysine (CML), RAGE, nitrotyrosine, Rac1, and MR levels in the kidneys and reduced UAE in DOCA mice. Aldosterone (Aldo) increased nitrotyrosine, CML, and RAGE gene expression in murine podocytes, whereas CML stimulated MR and Rac1 levels, which were blocked by RAGE-apt. The present study indicates the crosstalk between the AGE-RAGE axis and Aldo-MR system, suggesting that RAGE-apt may be a novel therapeutic tool for the treatment of MR-associated renal diseases.
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18 MeSH Terms
EP1 disruption attenuates end-organ damage in a mouse model of hypertension.
Bartlett CS, Boyd KL, Harris RC, Zent R, Breyer RM
(2012) Hypertension 60: 1184-91
MeSH Terms: Angiotensin II, Animals, Antihypertensive Agents, Aortic Aneurysm, Blood Pressure, Desoxycorticosterone, Disease Models, Animal, Female, Humans, Hydralazine, Hypertension, Kaplan-Meier Estimate, Kidney, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nephrectomy, Receptors, Prostaglandin E, EP1 Subtype
Show Abstract · Added December 21, 2013
Prostaglandin E(2) is a major prostanoid found in the kidney and vasculature contributing to the regulation of blood pressure. The prostaglandin E(2) receptor EP1 has been shown to contribute to hypertension by mediating angiotensin II-dependent vasoconstriction, although its precise role is incompletely characterized. Disruption of the EP1 receptor in C57BL/6J mice reduced the incidence of mortality during severe hypertension induced by uninephrectomy, deoxycorticosterone acetate, and angiotensin II. Mortality was dependent on all components of the model. Death was a result of aortic aneurysm rupture or occurred after development of anasarca, each of which was reduced in EP1-/- mice. Mean arterial pressure was increased in treated EP1+/+ and EP1-/- mice; however, this elevation was significantly lower in EP1-/- mice. Blood pressure reduction via administration of hydralazine phenocopied EP1-/- mice. Thus, reduction in blood pressure by disruption of EP1 reduced incidence of mortality and decreased organ damage, suggesting that EP1 receptor blockade may be a viable target for antihypertensive therapy.
3 Communities
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19 MeSH Terms
Ligand structural motifs can decouple glucocorticoid receptor transcriptional activation from target promoter occupancy.
Blind RD, Pineda-Torra I, Xu Y, Xu HE, Garabedian MJ
(2012) Biochem Biophys Res Commun 420: 839-44
MeSH Terms: 17-alpha-Hydroxyprogesterone, 3T3-L1 Cells, Adipocytes, Adipogenesis, Adrenal Cortex Hormones, Aldosterone, Animals, Cell Line, Tumor, Corticosterone, Desoxycorticosterone, Dexamethasone, Hydrocortisone, Ligands, Mice, Molecular Structure, Progesterone, Promoter Regions, Genetic, Protein Conformation, Rats, Receptors, Glucocorticoid, Transcriptional Activation
Show Abstract · Added August 18, 2015
Glucocorticoid (GC) induction of the tyrosine aminotransferase (TAT) gene by the glucocorticoid receptor (GR) is a classic model used to investigate steroid-regulated gene expression. Classic studies analyzing GC-induction of the TAT gene demonstrated that despite having very high affinity for GR, some steroids cannot induce maximal TAT enzyme activity, but the molecular basis for this phenomenon is unknown. Here, we used RT-PCR and chromatin immunoprecipitation to determine TAT mRNA accumulation and GR recruitment to the TAT promoter (TAT-GRE) in rat hepatoma cells induced by seven GR ligands: dexamethasone (DEX), cortisol (CRT), corticosterone (CCS), 11-deoxycorticosterone (DOC), aldosterone (ALD), progesterone (PRG) and 17-hydroxyprogesterone (17P). As expected, DEX, CRT, CCS and ALD all induced both TAT mRNA and GR recruitment to the TAT-GRE, while PRG and 17P did not. However, while DOC could not induce significant TAT mRNA, it did induce robust GR occupancy of the TAT-GRE. DOC also induced recruitment of the histone acetyltransferase p300 to the TAT-GRE as efficiently as DEX. These DOC-induced effects recapitulated at another GR target gene (sulfonyltransferase 1A1), and DOC also failed to promote the multiple changes in gene expression required for glucocorticoid-dependent 3T3-L1 adipocyte differentiation. Structural simulations and protease sensitivity assays suggest that DOC and DEX induce different conformations in GR. Thus, although steroids that bind GR with high affinity can induce GR and p300 occupancy of target promoters, they may not induce a conformation of GR capable of activating transcription.
Copyright © 2012 Elsevier Inc. All rights reserved.
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21 MeSH Terms
Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction.
Silberman GA, Fan TH, Liu H, Jiao Z, Xiao HD, Lovelock JD, Boulden BM, Widder J, Fredd S, Bernstein KE, Wolska BM, Dikalov S, Harrison DG, Dudley SC
(2010) Circulation 121: 519-28
MeSH Terms: Animals, Biopterin, Calcium-Binding Proteins, Desoxycorticosterone, Disease Models, Animal, Heart Failure, Diastolic, Hypertension, Male, Mice, Mice, Inbred C57BL, Myocardium, Nephrectomy, Nitric Oxide, Nitric Oxide Synthase, Oxygen, Peptidyl-Dipeptidase A, Superoxides, Ventricular Dysfunction, Left
Show Abstract · Added December 10, 2013
BACKGROUND - Heart failure with preserved ejection fraction is 1 consequence of hypertension and is caused by impaired cardiac diastolic relaxation. Nitric oxide (NO) is a known modulator of cardiac relaxation. Hypertension can lead to a reduction in vascular NO, in part because NO synthase (NOS) becomes uncoupled when oxidative depletion of its cofactor tetrahydrobiopterin (BH(4)) occurs. Similar events may occur in the heart that lead to uncoupled NOS and diastolic dysfunction.
METHODS AND RESULTS - In a hypertensive mouse model, diastolic dysfunction was accompanied by cardiac oxidation, a reduction in cardiac BH(4), and uncoupled NOS. Compared with sham-operated animals, male mice with unilateral nephrectomy, with subcutaneous implantation of a controlled-release deoxycorticosterone acetate pellet, and given 1% saline to drink were mildly hypertensive and had diastolic dysfunction in the absence of systolic dysfunction or cardiac hypertrophy. The hypertensive mouse hearts showed increased oxidized biopterins, NOS-dependent superoxide production, reduced NO production, and dephosphorylated phospholamban. Feeding hypertensive mice BH(4) (5 mg/d), but not treating with hydralazine or tetrahydroneopterin, improved cardiac BH(4) stores, phosphorylated phospholamban levels, and diastolic dysfunction. Isolated cardiomyocyte experiments revealed impaired relaxation that was normalized with short-term BH(4) treatment. Targeted cardiac overexpression of angiotensin-converting enzyme also resulted in cardiac oxidation, NOS uncoupling, and diastolic dysfunction in the absence of hypertension.
CONCLUSIONS - Cardiac oxidation, independently of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction. BH(4) may represent a possible treatment for diastolic dysfunction.
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18 MeSH Terms
O-GlcNAcylation contributes to augmented vascular reactivity induced by endothelin 1.
Lima VV, Giachini FR, Carneiro FS, Carneiro ZN, Saleh MA, Pollock DM, Fortes ZB, Carvalho MH, Ergul A, Webb RC, Tostes RC
(2010) Hypertension 55: 180-8
MeSH Terms: Acetylglucosamine, Animals, Aorta, Thoracic, Atrasentan, Blood Pressure, Blotting, Western, Desoxycorticosterone, Drug Synergism, Endothelin-1, Glycoproteins, Glycosylation, Hypertension, In Vitro Techniques, Male, N-Acetylglucosaminyltransferases, Phenylephrine, Pyrrolidines, Rats, Rats, Wistar, Time Factors, Vasoconstriction, Vasoconstrictor Agents
Show Abstract · Added July 31, 2014
O-GlcNAcylation augments vascular contractile responses, and O-GlcNAc-proteins are increased in the vasculature of deoxycorticosterone-acetate salt rats. Because endothelin 1 (ET-1) plays a major role in vascular dysfunction associated with salt-sensitive forms of hypertension, we hypothesized that ET-1-induced changes in vascular contractile responses are mediated by O-GlcNAc modification of proteins. Incubation of rat aortas with ET-1 (0.1 mumol/L) produced a time-dependent increase in O-GlcNAc levels and decreased expression of O-GlcNAc transferase and beta-N-acetylglucosaminidase, key enzymes in the O-GlcNAcylation process. Overnight treatment of aortas with ET-1 increased phenylephrine vasoconstriction (maximal effect [in moles]: 19+/-5 versus 11+/-2 vehicle). ET-1 effects were not observed when vessels were previously instilled with anti-O-GlcNAc transferase antibody or after incubation with an O-GlcNAc transferase inhibitor (3-[2-adamantanylethyl]-2-[{4-chlorophenyl}azamethylene]-4-oxo-1,3-thiazaperhyd roine-6-carboxylic acid; 100 mumol/L). Aortas from deoxycorticosterone-acetate salt rats, which exhibit increased prepro-ET-1, displayed increased contractions to phenylephrine and augmented levels of O-GlcNAc proteins. Treatment of deoxycorticosterone-acetate salt rats with an endothelin A antagonist abrogated augmented vascular levels of O-GlcNAc and prevented increased phenylephrine vasoconstriction. Aortas from rats chronically infused with low doses of ET-1 (2 pmol/kg per minute) exhibited increased O-GlcNAc proteins and enhanced phenylephrine responses (maximal effect [in moles]: 18+/-2 versus 10+/-3 control). These changes are similar to those induced by O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate, an inhibitor of beta-N-acetylglucosaminidase. Systolic blood pressure (in millimeters of mercury) was similar between control and ET-1-infused rats (117+/-3 versus 123+/-4 mm Hg; respectively). We conclude that ET-1 indeed augments O-GlcNAc levels and that this modification contributes to the vascular changes induced by this peptide. Increased vascular O-GlcNAcylation by ET-1 may represent a mechanism for hypertension-associated vascular dysfunction or other pathological conditions associated with increased levels of ET-1.
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22 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.
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18 MeSH Terms
Regulation of renal cortical cyclooxygenase-2 in young rats.
Zhang MZ, Wang SW, Cheng H, Zhang Y, McKanna JA, Harris RC
(2003) Am J Physiol Renal Physiol 285: F881-8
MeSH Terms: Aging, Aldosterone, Animals, Animals, Newborn, Animals, Suckling, Corticosterone, Cyclooxygenase 2, Desoxycorticosterone, Isoenzymes, Kidney Cortex, Prostaglandin-Endoperoxide Synthases, Rats, Rats, Sprague-Dawley, Sodium Chloride, Dietary, Weaning
Show Abstract · Added December 10, 2013
Cyclooxygenase-2 (COX-2) is involved in kidney morphogenesis and is transiently elevated in the immature kidney. In adult rats, renal cortical COX-2 expression is tonically suppressed by mineralocorticoids (MC) and glucocorticoids (GC) and induced by chronic salt restriction. Young rats have low levels of GC and are in a state of relative volume depletion. The present study was designed to investigate the mechanisms underlying elevated cortical COX-2 expression in the immature kidney. Supplementation of GC or MC suppressed cortical COX-2 expression in suckling rats. GC suppression was significantly, but not completely, prevented by either an MC receptor antagonist or a GC receptor antagonist. MC suppression was completely prevented by a mineralocorticoid receptor antagonist. Salt supplementation suppressed cortical COX-2 expression in a dose- and time-dependent pattern in the suckling rats. Cortical COX-2 expression in the weanling rats was upregulated by a low-salt diet and downregulated by a high-salt diet. These results suggest that relative volume depletion and reduced GC levels are involved in elevated cortical COX-2 expression in the immature rodent kidney.
1 Communities
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15 MeSH Terms
Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension.
Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG
(2003) J Clin Invest 111: 1201-9
MeSH Terms: Animals, Biopterin, Desoxycorticosterone, Endothelium, Vascular, Hydrogen Peroxide, Hypertension, Male, Mice, Mice, Inbred C57BL, NADPH Oxidases, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Oxidation-Reduction, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species, Superoxides, Vasodilation
Show Abstract · Added March 26, 2019
Tetrahydrobiopterin is a critical cofactor for the NO synthases, and in its absence these enzymes become "uncoupled," producing reactive oxygen species (ROSs) rather than NO. In aortas of mice with deoxycorticosterone acetate-salt (DOCA-salt) hypertension, ROS production from NO synthase is markedly increased, and tetrahydrobiopterin oxidation is evident. Using mice deficient in the NADPH oxidase subunit p47(phox) and mice lacking either the endothelial or neuronal NO synthase, we obtained evidence that hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase (eNOS). This decreases NO production and increases ROS production from eNOS. Treatment of mice with oral tetrahydrobiopterin reduces vascular ROS production, increases NO production as determined by electron spin resonance measurements of nitrosyl hemoglobin, and blunts the increase in blood pressure due to DOCA-salt hypertension. Endothelium-dependent vasodilation is only minimally altered in vessels of mice with DOCA-salt hypertension but seems to be mediated by hydrogen peroxide released from uncoupled eNOS, since it is inhibited by catalase. Tetrahydrobiopterin oxidation may represent an important abnormality in hypertension. Treatment strategies that increase tetrahydrobiopterin or prevent its oxidation may prove useful in preventing vascular complications of this common disease.
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MeSH Terms
Mineralocorticoid regulation of cyclooxygenase-2 expression in rat renal medulla.
Zhang MZ, Hao CM, Breyer MD, Harris RC, McKanna JA
(2002) Am J Physiol Renal Physiol 283: F509-16
MeSH Terms: Adrenalectomy, Animals, Blotting, Western, Cells, Cultured, Cyclooxygenase 2, Desoxycorticosterone, Diabetes Insipidus, Epithelial Cells, Female, Homeostasis, Isoenzymes, Kidney Medulla, Male, Mineralocorticoid Receptor Antagonists, Mineralocorticoids, Prostaglandin-Endoperoxide Synthases, Rats, Rats, Brattleboro, Rats, Sprague-Dawley, Receptors, Glucocorticoid, Receptors, Mineralocorticoid, Spironolactone
Show Abstract · Added December 10, 2013
The renal inner medulla and its distal one-third, the papilla, are major sites of prostanoid synthesis involved in water and electrolyte homeostasis. These sites contain variable levels of cyclooxygenase (COX)-2, a key prostaglandin synthase enzyme that is sensitive to adrenal steroids. Immunoreactive renal medullary COX-2, restricted to interstitial cells in control adult rats, shows a gradient of intense staining at the tip of the papilla that gradually diminishes to undetectable levels in the proximal inner medulla. We used adrenalectomy (ADX) and steroid replacement to investigate the effects of steroids on papillary COX-2. Immunoblots demonstrate that papillary COX-2 was reduced by one-half after 2 wk ADX; glucocorticoid replacement ameliorated the decline but not to control levels. Mineralocorticoid (deoxycorticosterone acetate; DOCA) replacement stimulated papillary COX-2 more than fivefold over control; both the intensity of immunostaining and the numbers of COX-2-positive cells in the inner medulla increased. Similar stimulation of papillary COX-2 resulted from DOCA treatment of normal control rats, but the response was blunted in rats fed a low-salt diet and absent in Brattleboro rats. DOCA treatment of mouse renal medullary interstitial cells in culture had no effect, but increased tonicity of the culture medium with NaCl caused strong upregulation of COX-2. Urea, a permeant molecule, had no effect. Together, these results suggest that mineralocorticoids lead to upregulation of COX-2 in rat renal medulla by indirect pathways, probably involving induced electrolyte hypertonicity in the interstitial fluid.
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22 MeSH Terms
Structure/function relationship of CYP11B1 associated with Dahl's salt-resistant rats--expression of rat CYP11B1 and CYP11B2 in Escherichia coli.
Nonaka Y, Fujii T, Kagawa N, Waterman MR, Takemori H, Okamoto M
(1998) Eur J Biochem 258: 869-78
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Cytochrome P-450 CYP11B2, DNA Primers, Desoxycorticosterone, Immunoblotting, Molecular Sequence Data, Molecular Structure, Mutation, Polymerase Chain Reaction, Rats, Rats, Inbred Dahl, Recombinant Proteins, Steroid 11-beta-Hydroxylase, Steroid Hydroxylases, Steroids, Structure-Activity Relationship, Substrate Specificity
Show Abstract · Added February 12, 2015
Dahl's salt-resistant normotensive rats (DR rats) have been previously reported to express cytochrome P-450 (CYP11B1) containing five missense mutations [Matsukawa, N., Nonaka, Y., Higaki, J., Nagano, M., Mikami H., Ogihara, T. & Okamoto, M. (1993) J. Biol. Chem. 268, 9117-9121]. To investigate structure-function relationships of CYP11B, wild-type rat CYP11B1 and CYP11B2 and DR-CYP11B1 (mutant CYP11B1 in Dahl's salt-resistant rats) have been successfully expressed in Escherichia coli. Steroid 11beta-hydroxylase (11beta-OHase) activity observed with DR-CYP11B1 was similar to that of wild-type CYP11B1, while 18-hydroxylase (18-OHase) activity of DR-CYP11B1 was lower than that of wild-type CYP11B1. Mutant CYP11B1s containing a single or a double amino acid substitution associated with DR-CYP11B1 have been also expressed in E. coli to investigate effects of the substitutions on enzymatic activity. Each of the single mutant enzymes showed lower 18-OHase activity than wild-type CYP11B1, but not as low as DR-CYP11B1. A double mutant CYP11B1 with V381L and I384L showed 18-OHase activity at a similar low level to that of DR-CYP11B1. The 19-hydroxylation (19-OHase) activity of DR-CYP11B1 was about one-third of that of the wild-type enzyme and this low activity appeared due to the V443M mutation. These results suggest that three of five amino acid substitutions present in DR-CYP11B1 account for the decreased 18-OHase and 19-OHase activities. A decrease in these enzyme activities may be responsible for the normotension of the DR rats when fed a high-salt diet.
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19 MeSH Terms