Chronic endothelial dopamine receptor stimulation improves endothelial function and hemodynamics in autosomal dominant polycystic kidney disease

IF 14.8 1区 医学 Q1 UROLOGY & NEPHROLOGY
Audrey Dumont , Mouad Hamzaoui , Déborah Groussard , Michèle Iacob , Dominique Bertrand , Isabelle Remy-Jouet , Mélanie Hanoy , Frank Le Roy , Laurence Chevalier , Christoph Enzensperger , Hans-Dieter Arndt , Sylvanie Renet , Anaïs Dumesnil , Emilie Lévêque , Thomas Duflot , Valéry Brunel , Aurore Michel-Després , Marie-Pierre Audrézet , Vincent Richard , Robinson Joannidès , Jérémy Bellien
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Abstract

Altered polycystin-mediated endothelial flow mechanosensitivity contributes to the development of hypertension and cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD). Stimulation of endothelial type 5 dopamine receptors (DR5) can acutely compensate for the endothelial consequences of polycystin deficiency, but the chronic impact of this approach must be evaluated in ADPKD. Nineteen patients with ADPKD on standard of care therapy were randomized to receive a 2-month treatment with the DR agonist rotigotine using transdermal patches, nine at 2 mg/24hours and ten at 4 mg/24hours or while ten were untreated. Rotigotine at the dose of 4 mg/24hours significantly increased nitric oxide release (nitrite levels from 10±30 to 46±34 nmol/L) and radial artery endothelium-dependent flow-mediated dilatation (from 16.4±6.3 to 22.5±7.3%) in response to hand skin heating. Systemic hemodynamics were not significantly modified but aplanation tonometry showed that rotigotine at 4 mg/24hours reduced aortic augmentation index and pulse pressure without affecting carotid-to femoral pulse wave velocity. Plasma creatinine and urea, urinary cyclic AMP, which contributes to cyst growth in ADPKD and copeptin, a surrogate marker of vasopressin, were not affected by rotigotine. In mice with a specific deletion of polycystin-1 in endothelial cells, chronic infusion of the peripheral DR5 agonist fenoldopam also improved mesenteric artery flow-mediated dilatation and reduced blood pressure. Thus, our study demonstrates that in patients with ADPKD, chronic administration of rotigotine improves conduit artery endothelial function through the restoration of flow-induced nitric oxide release as well as hemodynamics suggesting that endothelial DR5 activation may represent a promising pharmacological approach to prevent cardiovascular complications of ADPKD.

Abstract Image

慢性内皮多巴胺受体刺激可改善常染色体显性多囊肾的内皮功能和血液动力学。
多囊卵巢蛋白介导的内皮血流机械敏感性改变导致常染色体显性多囊肾(ADPKD)患者出现高血压和心血管并发症。刺激内皮 5 型多巴胺受体(DR5)可迅速补偿多囊卵巢素缺乏对内皮的影响,但必须评估这种方法对 ADPKD 的慢性影响。19名接受标准治疗的ADPKD患者被随机分配接受为期2个月的DR激动剂罗替戈汀透皮贴剂治疗,其中9人的剂量为2毫克/24小时,10人的剂量为4毫克/24小时,10人未接受治疗。罗替戈汀的剂量为 4 毫克/24 小时,它能显著增加一氧化氮的释放(亚硝酸盐水平从 10±30 升至 46±34 毫摩尔/升),以及手部皮肤加热时桡动脉内皮依赖性血流介导的扩张(从 16.4±6.3% 升至 22.5±7.3%)。全身血液动力学没有明显变化,但平面测压显示,4 毫克/24 小时的轮状戈汀可降低主动脉增强指数和脉压,而不影响颈动脉至股动脉的脉搏波速度。罗替戈汀对血浆肌酐和尿素、尿环磷酸腺苷(有助于 ADPKD 中囊肿的生长)以及血管加压素的替代标记物 copeptin 均无影响。在内皮细胞中特异性缺失聚胞素-1的小鼠中,长期输注外周DR5激动剂非诺多泮也能改善肠系膜动脉血流介导的扩张并降低血压。因此,我们的研究表明,在 ADPKD 患者中,长期给予罗替戈汀可通过恢复血流诱导的一氧化氮释放和血流动力学改善导管动脉内皮功能,这表明内皮 DR5 激活可能是预防 ADPKD 心血管并发症的一种很有前景的药理学方法。
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来源期刊
Kidney international
Kidney international 医学-泌尿学与肾脏学
CiteScore
23.30
自引率
3.10%
发文量
490
审稿时长
3-6 weeks
期刊介绍: Kidney International (KI), the official journal of the International Society of Nephrology, is led by Dr. Pierre Ronco (Paris, France) and stands as one of nephrology's most cited and esteemed publications worldwide. KI provides exceptional benefits for both readers and authors, featuring highly cited original articles, focused reviews, cutting-edge imaging techniques, and lively discussions on controversial topics. The journal is dedicated to kidney research, serving researchers, clinical investigators, and practicing nephrologists.
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