-
Pregnancy Hypertension Apr 2017Placental FasL is up-regulated in women with HELLP (hemolysis elevated liver enzyme and low platelet) syndrome and has been proposed to contribute to the liver damage...
INTRODUCTION
Placental FasL is up-regulated in women with HELLP (hemolysis elevated liver enzyme and low platelet) syndrome and has been proposed to contribute to the liver damage seen in these patients.
OBJECTIVE
This study aimed to determine if an experimental rodent model of HELLP also had dysregulation of Fas/FasL compared to normal pregnant (NP) rats. We also set out to determine if blockade of the endothelin system regulated Fas/FasL expression in HELLP rats.
STUDY DESIGN
On gestational day (GD) 12, sEng (7ug/kg) and sFlt-1 (4.7ug/kg) infusion began via mini-osmotic pump into NP rats. On GD19 plasma and tissue were collected and FasL and Fas were measured via enzyme linked immunosorbent assay and gene expression via real-time PCR.
RESULTS
HELLP rats had significantly more circulating and placental FasL compared to NP rats, whereas hepatic FasL was decreased and placental Fas was increased compared to NP rats. Administration of an endothelin A receptor antagonist (ET) beginning on GD12 significantly decreased placental expression of Fas in HELLP rats. Liver mRNA transcript of Fas was significantly increased in HELLP rats compared to NP rats.
CONCLUSION
These data suggest that rats in this experimental model of HELLP syndrome have abnormal expression of the Fas/FasL system. Future studies will examine the sources of Fas/FasL dysregulation in this model and if blockade could reduce some of the inflammation and hypertension associated with HELLP syndrome.
Topics: Animals; Atrasentan; Disease Models, Animal; Endoglin; Endothelin A Receptor Antagonists; Fas Ligand Protein; Female; Gene Expression Regulation; HELLP Syndrome; Liver; Placenta; Pregnancy; Pyrrolidines; RNA, Messenger; Rats, Sprague-Dawley; Time Factors; Vascular Endothelial Growth Factor Receptor-1; fas Receptor
PubMed: 28501275
DOI: 10.1016/j.preghy.2017.02.004 -
Laboratory Investigation; a Journal of... Mar 2017Although endothelin (ET)-1 has been shown to upregulate nerve growth factor (NGF) expression, the molecular mechanisms are largely unknown. Phosphatidylinositol 3-kinase...
Although endothelin (ET)-1 has been shown to upregulate nerve growth factor (NGF) expression, the molecular mechanisms are largely unknown. Phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase (GSK)-3β signal has been implicated in the regulation of NGF. We investigated whether selective ET receptor blockers attenuated cardiac sympathetic reinnervation through restoring PI3K/Akt/GSK-3β activity. After ligation of the left anterior descending artery, male Wistar rats were randomized to either vehicle, atrasentan (an ET receptor antagonist) or A-192621 (an ET receptor antagonist) for 4 weeks. Sympathetic hyperinnervation after infarction was confirmed by myocardial norepinephrine measurement and immunofluorescent analysis. Post infarction was associated with increased reactive oxygen species (ROS), as measured by myocardial superoxide levels and dihydroethidine fluorescence staining. This was paralleled by a significant upregulation of NGF expression on mRNA and protein levels in the vehicle-treated rats, which reduced after administering atrasentan, not A-192621. Arrhythmic scores in the vehicle-treated rats were significantly higher than those treated with atrasentan. In an in vivo study atrasentan-induced decreased NGF was associated with activation of PI3K/Akt signaling pathway, which was further confirmed by the ex vivo study showing the restoration of NGF levels after coadministration of PI3K inhibitors (wortmannin and LY294002). Lithium chloride, an inhibitor of GSK-3β, did not provide additional attenuated NGF levels compared with atrasentan alone. Finally, atrasentan-attenuated NGF levels were reversed in the presence of peroxynitrite generator. ET receptor antagonism is a mediator to attenuate sympathetic hyperinnervation probably through restoration of PI3K/Akt/GSK-3β/ROS signaling pathway, a potential pharmacological target for arrhythmias after infarction.
Topics: Animals; Arrhythmias, Cardiac; Atrasentan; Blotting, Western; Endothelin Receptor Antagonists; Enzyme Inhibitors; Glycogen Synthase Kinase 3 beta; Heart; Male; Myocardial Infarction; Myocardium; Nerve Growth Factor; Norepinephrine; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrrolidines; Random Allocation; Rats, Wistar; Reactive Oxygen Species; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sympathetic Nervous System
PubMed: 27991911
DOI: 10.1038/labinvest.2016.138 -
The Journal of Pharmacology and... Nov 2014Experiments determined whether the combination of endothelin A (ETA) receptor antagonist [ABT-627, atrasentan;...
Experiments determined whether the combination of endothelin A (ETA) receptor antagonist [ABT-627, atrasentan; (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid] and a thiazide diuretic (chlorthalidone) would be more effective at lowering blood pressure and reducing renal injury in a rodent model of metabolic syndrome compared with either treatment alone. Male Dahl salt-sensitive rats were fed a high-fat (36% fat), high-salt (4% NaCl) diet for 4 weeks. Separate groups of rats were then treated with vehicle (control), ABT-627 (ABT; 5 mg/kg per day, in drinking water), chlorthalidone (CLTD; 5 mg/kg per day, in drinking water), or both ABT plus CLTD. Mean arterial pressure (MAP) was recorded continuously by telemetry. After 4 weeks, both ABT and CLTD severely attenuated the development of hypertension, whereas the combination further reduced MAP compared with ABT alone. All treatments prevented proteinuria. CLTD and ABT plus CLTD significantly reduced nephrin (a podocyte injury marker) and kidney injury molecule-1 (a tubulointerstitial injury marker) excretion. ABT, with or without CLTD, significantly reduced plasma 8-oxo-2'-deoxyguanosine, a measure of DNA oxidation, whereas CLTD alone had no effect. All treatments suppressed the number of ED1(+) cells (macrophages) in the kidney. Plasma tumor necrosis factor receptors 1 and 2 were reduced only in the combined ABT and CLTD group. These results suggest that ABT and CLTD have antihypertensive and renal-protective effects in a model of metabolic syndrome that are maximally effective when both drugs are administered together. The findings support the hypothesis that combined ETA antagonist and diuretic treatment may provide therapeutic benefit for individuals with metabolic syndrome consuming a Western diet.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antihypertensive Agents; Arterial Pressure; Atrasentan; Cell Adhesion Molecules; Chlorthalidone; Deoxyguanosine; Disease Models, Animal; Diuretics; Drug Combinations; Endothelin A Receptor Antagonists; Endothelins; Hypertension; Inflammation; Kidney Diseases; Male; Membrane Proteins; Metabolic Syndrome; Oxidative Stress; Proteinuria; Pyrrolidines; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Receptor, Endothelin A; Sodium Chloride, Dietary
PubMed: 25189702
DOI: 10.1124/jpet.114.215566 -
Hong Kong Medical Journal = Xianggang... Jun 2024
PubMed: 38918067
DOI: 10.12809/hkmj245162 -
Clinical Journal of the American... Jun 2020
Topics: Atrasentan; Diabetic Nephropathies; Humans; Reproducibility of Results
PubMed: 32019759
DOI: 10.2215/CJN.08540719 -
Scientific Reports Apr 2018This corrects the article DOI: 10.1038/srep19979.
This corrects the article DOI: 10.1038/srep19979.
PubMed: 29623952
DOI: 10.1038/srep46965 -
Frontiers in Physiology 2019Our previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ET) blocker atrasentan added to the...
OBJECTIVE
Our previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ET) blocker atrasentan added to the renin-angiotensin system (RAS) blockade had renoprotective effects in a model of chronic kidney disease (CKD) induced by partial nephrectomy. Since ET blockade is known to cause edema, we were interested whether diuretic treatment added to this therapy would be beneficial.
DESIGN AND METHODS
Partial nephrectomy (NX) was performed at the age of 3 months in TGR rats which were subjected to: (i) RAS blockade alone (angiotensin receptor blocker losartan and angiotensin converting enzyme inhibitor trandolapril), (ii) combined RAS (losartan and trandolapril) and ET receptor blockade (atrasentan), or (iii) diuretic (hydrochlorothiazide) added to the combined RAS + ET blockade for 50 weeks following NX.
RESULTS
At the end of the study systolic blood pressure and cardiac hypertrophy were similarly decreased in all treated groups. Survival was significantly improved by ET receptor blockade added to RAS blockade with no further effects of diuretic treatment. However, additional diuretic treatment combined with RAS + ET blockade decreased body weight and had beneficial renoprotective effects - reductions of both kidney weight and kidney damage markers. Proteinuria gradually increased in rats treated with RAS blockade alone, while it was substantially lowered by additional ET blockade. In rats treated with additional diuretic, proteinuria was progressively reduced throughout the experiment.
CONCLUSION
A diuretic added to the combined RAS and ET blockade has late renoprotective effects in CKD induced by partial nephrectomy in Ren-2 transgenic rats. The diuretic improved: renal function (evaluated as proteinuria and creatinine clearance), renal morphology (kidney mass, glomerular volume), and histological markers of kidney damage (glomerulosclerosis index, tubulointerstitial injury).
PubMed: 31620007
DOI: 10.3389/fphys.2019.01145 -
Physiological Research Oct 2019Our studies in hypertensive Ren-2 transgenic rats (TGR) demonstrated that chronic administration of atrasentan (ETA receptor antagonist) decreased blood pressure by...
Our studies in hypertensive Ren-2 transgenic rats (TGR) demonstrated that chronic administration of atrasentan (ETA receptor antagonist) decreased blood pressure by reduced Ca2+ influx through L-type voltage-dependent calcium channels (L-VDCC) and attenuated angiotensin II-dependent vasoconstriction. We were interested whether bosentan (nonselective ET(A)/ET(B) receptor antagonist) would have similar effects. Young 4-week-old (preventive study) and adult 8-week-old (therapeutic study) heterozygous TGR and their normotensive Hannover Sprague-Dawley (HanSD) controls were fed normal-salt (NS, 0.6 % NaCl) or high-salt (HS, 2 % NaCl) diet for 8 weeks. An additional group of TGR fed HS was treated with bosentan (100 mg/kg/day). Bosentan had no effect on BP of TGR fed high-salt diet in both the preventive and therapeutic studies. There was no difference in the contribution of angiotensin II-dependent and sympathetic vasoconstriction in bosentan-treated TGR compared to untreated TGR under the condition of high-salt intake. However, bosentan significantly reduced NO-dependent vasodilation and nifedipine-sensitive BP component in TGR on HS diet. A highly important correlation of nifedipine-induced BP change and the BP after L-NAME administration was demonstrated. Although bosentan did not result in any blood pressure lowering effects, it substantially influenced NO-dependent vasodilation and calcium influx through L-VDCC in the heterozygous TGR fed HS diet. A significant correlation of nifedipine-induced BP change and the BP after L-NAME administration suggests an important role of nitric oxide in the closure of L-type voltage dependent calcium channels.
Topics: Animals; Blood Pressure; Bosentan; Calcium Channels, L-Type; Calcium Signaling; Disease Models, Animal; Endothelin Receptor Antagonists; Heterozygote; Hypertension; Male; Nitric Oxide; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Sodium Chloride, Dietary; Vasodilation
PubMed: 31424254
DOI: 10.33549/physiolres.934192 -
Clinical Genitourinary Cancer Dec 2017Phase 2 trials evaluating new agents for metastatic castration-resistant prostate cancer (mCRPC) have relied on bone scan and prostate-specific antigen changes to assess...
BACKGROUND
Phase 2 trials evaluating new agents for metastatic castration-resistant prostate cancer (mCRPC) have relied on bone scan and prostate-specific antigen changes to assess activity. Given the increasing detection of measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST) changes warrant consideration to evaluate activity. We validated the association of RECIST 1.0 changes with survival in men with mCRPC receiving docetaxel.
PATIENTS AND METHODS
Data for men with measurable disease from the Southwest Oncology Group (SWOG) S0421, a phase 3 trial in men with mCRPC receiving docetaxel and prednisone plus placebo or atrasentan, were used. Cox proportional hazards regression was used to evaluate the association of RECIST 1.0 outcomes within 120 days, ie, unconfirmed partial response (uPR), stable disease, and progressive disease (PD), with overall survival (OS) from day 120, adjusted for prognostic factors.
RESULTS
Overall, 326 men were evaluable for landmark analysis, of whom 23 had PD, 230 stable disease, and 73 uPR. OS beyond day 120 was significantly different (P = .004) among these subgroups, with median (95% confidence interval) OS of 7.1 (3.5-8.8), 13.4 (11.4-15.6), and 16.3 (10.0-19.6) months for those with PD, stable disease, and uPR, respectively. In a multivariable model, the hazard ratio (95% confidence interval) for patients with PD was 2.47 (1.42-4.29) compared to patients with an uPR (P = .002).
CONCLUSION
The association of RECIST 1.0 changes with OS in men with mCRPC receiving docetaxel was validated. Given limitations of bone scan and prostate-specific antigen alterations, improvements in objective RECIST 1.0 changes should be reported in phase 2 trials before launching phase 3 trials.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Controlled Clinical Trials as Topic; Docetaxel; Double-Blind Method; Humans; Male; Middle Aged; Prednisone; Prostatic Neoplasms, Castration-Resistant; Response Evaluation Criteria in Solid Tumors; Survival Analysis; Taxoids
PubMed: 28579151
DOI: 10.1016/j.clgc.2017.05.014 -
PLoS Medicine Feb 2017Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension.
METHODS AND FINDINGS
To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 μg/kg/d and then 60 min at 30 μg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population.
CONCLUSIONS
Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01640964.
Topics: Adolescent; Adult; Aged; Animals; Female; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Liver Cirrhosis; Male; Middle Aged; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Regional Blood Flow; Relaxin; Scotland; Young Adult
PubMed: 28245243
DOI: 10.1371/journal.pmed.1002248