Regulation of Renal Hemodynamics by Adenosine Mediated Coincident Signaling

腺苷介导的同步信号传导对肾血流动力学的调节

• 批准号: 8538375
• 负责人: JONATHAN D VERRIER
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538375
• 关键词: Address; Adenosine; Adenosine A1 Receptor; Adrenergic Receptor; Adverse effects; Animals; Applications Grants; Attenuated; Chronic; Chronic Kidney Failure; Clinical; Conflict (Psychology); Congestive; Cyclic AMP-Dependent Protein Kinases; Disease; Disease Management; Diuretics; Enzymes; Fellowship; Glomerular Filtration Rate; Heart; Heart Diseases; Heart failure; Hypertension; In Vitro; Intervention; Kidney; Knock-out; Knockout Mice; Laboratories; Liver; Liver Dysfunction; Location; Mediating; Molecular; Mus; Nerve; Neuroeffector Junction; Norepinephrine; Pathway interactions; Patients; Pharmaceutical Preparations; Phospholipase C; Physicians; Physiological; Physiology; Play; Protein Kinase C; Public Health; Purinergic P1 Receptors; Regulation; Renal Blood Flow; Reporting; Resistance; Role; Scientist; Signal Pathway; Signal Transduction; Site; Sodium; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Training; Tubular formation; adenosine receptor activation; citrate carrier; extracellular; hemodynamics; in vivo; interest; kidney vascular structure; neurotransmission; novel; patient population; receptor; reconstitution; research study; response; vasoconstriction

DESCRIPTION (provided by applicant): Diuretics are used as a pharmacological therapeutic intervention in diseases including hypertension, heart failure, liver dysfunction and chronic kidney disease. These disease states are associated with increased renal sympathetic tone, which in turn, ultimately leads to decreases in both renal blood flows (RBF) and glomerular filtration rate (GFR). Unfortunately, diuretic treatment has been shown to also increase renal sympathetic tone thus adding to the observed deleterious effects on kidney hemodynamics already present in these patients. This effect could be a contributing mechanism underlying the conditions of diuretic resistance and intolerance which limit the therapeutic potential of the current diuretics. To address this significant public health issue, effort is being put forth to develop new diuretic drugs suitable for chronic treatment that preserve renal hemodynamics. Observations from our laboratory demonstrate that BG9928, a selective A1 adenosine receptor (A1AR) antagonist, reduces renal sympathetic nerve stimulation (RSNS)-induced renal vasoconstriction. These findings suggest that A1AR activation in the renal neuroeffector junction potentiates renal sympathetic neurotransmission. RSNS has been shown to increase the concentration of norepinephrine (NE) and ATP (also the enzymes that metabolize ATP to adenosine) in the neuroeffector junction. Since the precise role that adenosine plays in modulating renal sympathetic neurotransmission remains undefined, our overall objective is to examine the mechanism by which adenosine enhances the vasoconstrictive response to RSNS. In conjunction, we will demonstrate the means by which selective A1AR antagonists exert their diuretic effects while preserving favorable renal hemodynamics. Since pre-junctional A1ARs are inhibitory, we suggest here that it is the post-junctional A1ARs that are the predominant site of action of adenosine in response to RSNS. Also propose that adenosine potentiates NE's vasoconstrictive actions via coincident signaling (convergence of pathways). To test our hypothesis, we will use multiple approaches/techniques providing considerable training potential for this fellowship application. 1) We will demonstrate that antagonism of only the A1AR subtype will reduce RSNS-induced vasoconstriction in the presence of released NE. 2) We will show using A1AR knock-out animals that reconstitution of only the post-junction receptors restores the wild-type response to RSNS. 3) Using isolated kidneys and in vitro experiments, we will demonstrate the precise mechanism of coincident signaling between adenosine and NE that increases the vasoconstrictive response to RSNS. The completion of this project, in addition to the significant training potential, will identify a previously unappreciated mechanism for adenosine in regulating renal hemodynamics and support for the use of A1AR antagonists in conditions with elevated renal sympathetic tone. The information obtained from these experiments will be of interest to a broad audience, ranging from basic scientists studying renal physiology to clinical physicians evaluating potential therapeutic benefit and/or complications of diuretic treatment.

描述（由申请人提供）：利尿剂用于高血压、心力衰竭、肝功能障碍和慢性肾病等疾病的药物治疗干预。这些疾病状态与肾脏交感神经张力增加有关，这反过来最终导致肾血流量（RBF）和肾小球滤过率（GFR）降低。不幸的是，利尿剂治疗也增加了肾脏交感神经张力，从而增加了对这些患者已经存在的肾脏血流动力学的有害影响。这种效应可能是利尿剂抵抗和不耐受的潜在机制，从而限制了当前利尿剂的治疗潜力。为了解决这一重大的公共卫生问题，人们正在努力开发新的利尿剂，适用于慢性治疗，保持肾脏血流动力学。我们实验室的观察表明，BG9928是一种选择性A1腺苷受体（A1AR）拮抗剂，可减少肾交感神经刺激（RSNS）引起的肾血管收缩。这些发现表明A1AR在肾神经效应器交界处的激活增强了肾交感神经传递。RSNS已被证明可以增加神经效应接点的去甲肾上腺素（NE）和ATP（也是将ATP代谢为腺苷的酶）的浓度。由于腺苷在调节肾交感神经传递中的确切作用尚不清楚，我们的总体目标是研究腺苷增强RSNS血管收缩反应的机制。同时，我们将展示选择性A1AR拮抗剂在保持有利的肾血流动力学的同时发挥利尿作用的方法。由于连接前A1ARs具有抑制作用，我们认为连接后A1ARs是腺苷对RSNS反应的主要作用位点。还提出腺苷通过一致的信号传导（途径的收敛）增强NE的血管收缩作用。为了验证我们的假设，我们将使用多种方法/技术为该奖学金申请提供可观的培训潜力。1)我们将证明，仅A1AR亚型的拮抗作用将减少释放的NE存在时rsns诱导的血管收缩。2)我们将用A1AR敲除的动物证明，仅重建连接后受体可以恢复对RSNS的野生型反应。3)通过离体肾脏和体外实验，我们将证明腺苷和NE之间同步信号传导增加RSNS血管收缩反应的确切机制。这个项目的完成，除了重要的训练潜力，将确定一个以前未被认识的腺苷调节肾脏血流动力学的机制，并支持在肾交感神经张力升高的情况下使用A1AR拮抗剂。从这些实验中获得的信息将引起广泛的兴趣，从研究肾脏生理学的基础科学家到评估利尿剂治疗潜在治疗益处和/或并发症的临床医生。