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1.
Toxicol Appl Pharmacol ; 426: 115615, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102242

RESUMO

Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.


Assuntos
Atrasentana/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Cardiopatias/prevenção & controle , Nefropatias/prevenção & controle , Naftalenos/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Propionatos/uso terapêutico , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Animais , Atrasentana/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftalenos/farmacologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética
2.
Am J Pathol ; 191(5): 829-837, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33617784

RESUMO

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. In diabetic mice, reduced thrombomodulin function results in diabetic nephropathy (DN). Furthermore, thrombomodulin treatment reduces renal inflammation and fibrosis. Herein, thrombomodulin expression was examined in human kidney samples to investigate the possibility of targeting thrombomodulin in patients with DN. Glomerular thrombomodulin was analyzed together with the number of glomerular macrophages in 90 autopsied diabetic cases with DN, 55 autopsied diabetic cases without DN, and 37 autopsied cases without diabetes or kidney disease. Thrombomodulin mRNA was measured in glomeruli microdissected from renal biopsies from patients with DN and nondiabetic controls. Finally, glomerular thrombomodulin was measured in diabetic mice following treatment with the selective endothelin A receptor (ETAR) blocker, atrasentan. In diabetic patients, glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Reduced glomerular thrombomodulin was associated with an increased glomerular influx of macrophages. Blocking the ETAR with atrasentan restored glomerular thrombomodulin protein levels in diabetic mice to normal levels. The reduction in glomerular thrombomodulin in diabetes likely serves as an early proinflammatory step in the pathogenesis of DN. Thrombomodulin protein may be cleaved under diabetic conditions, leading to a compensatory increase in transcription. The nephroprotective effects of ETAR antagonists in diabetic patients may be attributed to the restoration of glomerular thrombomodulin.


Assuntos
Atrasentana/farmacologia , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/patologia , Antagonistas do Receptor de Endotelina A/farmacologia , Fibrose/patologia , Trombomodulina/metabolismo , Animais , Endotélio/patologia , Humanos , Inflamação/patologia , Rim/patologia , Glomérulos Renais/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Trombomodulina/efeitos dos fármacos , Trombomodulina/genética
3.
J Pharmacol Exp Ther ; 376(1): 98-105, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127751

RESUMO

The G protein-coupled estrogen receptor 1 (GPER1) mediates rapid estrogenic signaling. We recently reported that activation of GPER1 in the renal medulla evokes endothelin-1-dependent natriuresis in female, but not male, rats. However, the involvement of the ET receptors, ETA and ETB, underlying GPER1 natriuretic action remain unclear. In this study, we used genetic and pharmacologic methods to identify the contributions of ETA and ETB in mediating this female-specific natriuretic effect of renal medullary GPER1. Infusion of the GPER1-selective agonist G1 (5 pmol/kg per minute) into the renal medulla for 40 minutes increased Na+ excretion and urine flow in anesthetized female ETB-deficient (ETB def) rats and littermate controls but did not affect blood pressure or urinary K+ excretion in either group. Pretreatment with the selective ETA inhibitor ABT-627 (5 mg/kg, intravenous) abolished G1-induced natriuresis in ETB def rats. To further isolate the effects of inhibiting either receptor alone, we conducted the same experiments in anesthetized female Sprague-Dawley (SD) rats pretreated or not with ABT-627 and/or the selective ETB inhibitor A-192621 (10 mg/kg, intravenous). Neither antagonism of ETA nor antagonism of ETB receptor alone affected the G1-induced increase in Na+ excretion and urine flow in SD rats. However, simultaneous antagonism of both receptors completely abolished these effects. These data suggest that ETA and ETB receptors can mediate the natriuretic and diuretic response to renal medullary GPER1 activation in female rats. SIGNIFICANCE STATEMENT: Activation of G protein-coupled estrogen receptor 1 (GPER1) in the renal medulla of female rats evokes natriuresis via endothelin receptors A and/or B, suggesting that GPER1 and endothelin signaling pathways help efficient sodium excretion in females. Thus, GPER1 activation could be potentially useful to mitigate salt sensitivity in females.


Assuntos
Natriurese , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Atrasentana/farmacologia , Antagonistas dos Receptores de Endotelina/farmacologia , Feminino , Medula Renal/efeitos dos fármacos , Medula Renal/metabolismo , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/agonistas
4.
Expert Opin Investig Drugs ; 30(3): 253-262, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33356648

RESUMO

Introduction: Selective antagonists of Endothelin-1 receptors (ERA) have been tested in diabetic and nondiabetic chronic kidney disease (CKD). The SONAR trial (Study Of diabetic Nephropathy with AtRasentan) was the first randomized, phase 3, study assessing the long-term effect of ERA on CKD progression.Areas covered: We examine the ERA effects in proteinuric CKD. We discuss the results of the main clinical studies on ERA in CKD and offer an opinion on the findings of SONAR study and future perspectives in this field. We searched in PubMed and ISI Web of Science databases for including experimental and clinical studies that evaluated ERA in proteinuric CKD.Expert opinion: The SONAR study demonstrated that ERA confers protection against risk for CKD progression. This trial stimulated clinical research on ERA, to expand the therapeutic opportunities in CKD patients. Two novel phase 3 studies testing ERA in patients with glomerular disease are ongoing. Within the context of personalized medicine, we think it would be relevant to evaluate the effect of multiple treatments, including ERA, in proteinuric CKD patients. Testing ERA in clinical trials of novel design will also help at identifying the patients who would more benefit from these drugs.


Assuntos
Antagonistas do Receptor de Endotelina A/farmacologia , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Atrasentana/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Progressão da Doença , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor de Endotelina A/efeitos dos fármacos , Receptor de Endotelina A/metabolismo , Insuficiência Renal Crônica/fisiopatologia
5.
Am J Physiol Renal Physiol ; 318(5): F1295-F1305, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249614

RESUMO

Podocyte loss and proteinuria are both key features of human diabetic nephropathy (DN). The leptin-deficient BTBR mouse strain with the ob/ob mutation develops progressive weight gain, type 2 diabetes, and diabetic nephropathy that has many features of advanced human DN, including increased mesangial matrix, mesangiolysis, podocyte loss, and proteinuria. Selective antagonism of the endothelin-1 type A receptor (ETAR) by atrasentan treatment in combination with renin-angiotensin-aldosterone system inhibition with losartan has been shown to have the therapeutic benefit of lowering proteinuria in patients with DN, but the underlying mechanism for this benefit is not well understood. Using a similar therapeutic approach in diabetic BTBR ob/ob mice, this treatment regimen significantly increased glomerular podocyte number compared with diabetic BTBR ob/ob controls and suggested that parietal epithelial cells were a source for podocyte restoration. Atrasentan treatment alone also increased podocyte number but to a lesser degree. Mice treated with atrasentan demonstrated a reduction in proteinuria, matching the functional improvement reported in humans. This is a first demonstration that treatment with the highly selective ETAR antagonist atrasentan can lead to restoration of the diminished podocyte number characteristic of DN in humans and thereby underlies the reduction in proteinuria in patients with diabetes undergoing similar treatment. The benefit of ETAR antagonism in DN extended to a decrease in mesangial matrix as measured by a reduction in accumulations of collagen type IV in both the atrasentan and atrasentan + losartan-treated groups compared with untreated controls.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Atrasentana/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor de Endotelina A/farmacologia , Losartan/farmacologia , Podócitos/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Camundongos , Fosforilação , Podócitos/metabolismo , Podócitos/patologia , Proteinúria/metabolismo , Proteinúria/patologia , Proteinúria/prevenção & controle , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/metabolismo
6.
Eur J Pharmacol ; 852: 142-150, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30876973

RESUMO

Diabetic nephropathy (DN) is the most common complication of diabetes mellitus. Atrasentan (Atr) has potential therapeutic values for DN. MicroRNAs (miRNAs) function as vital regulators in the pathophysiology of kidney diseases including DN. Our present study aimed to further explore whether Atr could alleviate kidney injury by regulating microRNA-21(miR-21)/forkhead box O1 (FOXO1) in DN mouse models and cell models. Blood glucose concentration and ACR ratio were determined by matching commercial kits. MiR-21 and FOXO1 mRNA level was measured by RT-qPCR assay. Protein levels of FOXO1, LC3Ⅰ, LC3Ⅱ and p62 were measured by western blot assay. Cell apoptotic index was examined by flow cytometry. The interaction of miR-21 and FOXO1 was tested by bioinformatics analysis, luciferase assay and RIP assay. We found that Atr alleviated kidney injury by inhibiting miR-21 expression and promoting autophagy in DN mice. Moreover, miR-21 loss suppressed apoptosis and induced autophagy in high glucose (HG)-treated podocytes. And, Atr inhibited cell apoptosis and improved cell autophagic activity by downregulating miR-21 in HG-cultured podocytes. Moreover, FOXO1 was identified as a target of miR-21. MiR-21 exerted its pro-apoptosis and anti-autophagy effects by targeting FOXO1 in HG-cultured podocytes. Atr enhanced FOXO1 expression by downregulating miR-21 in HG-cultured podocytes. We concluded that Atr mitigated kidney injury in DN mice and alleviated HG-mediated apoptosis increase and autophagy inhibition in podocytes by regulating miR-21/FOXO1 axis, further elucidating the molecular basis by which Atr hampered DN progression.


Assuntos
Atrasentana/farmacologia , Proteína Forkhead Box O1/metabolismo , Glucose/farmacologia , MicroRNAs/genética , Podócitos/efeitos dos fármacos , Podócitos/patologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Podócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos
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