Sphingosine-1-phosphate in renal microvascular dysfunction of ischemia-reperfusion kidney injury

1-磷酸鞘氨醇在缺血再灌注肾损伤肾微血管功能障碍中的作用

• 批准号: 9239215
• 负责人: Zhengrong Guan
• 金额: $ 35.61万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-18 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239215
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Aftercare; Agonist; American; Biological Markers; Blood; Blood Vessels; Blood flow; Chronic Kidney Failure; Clinical; Data; Development; Dialysis patients; Enzymes; Event; Functional disorder; Genetic; Glomerular Filtration Rate; Goals; H218 Protein; Health Care Costs; In Vitro; Inflammation; Injury; Ischemia; Juxtamedullary Nephron; Kidney; Knock-out; Knockout Mice; Laser-Doppler Flowmetry; Lead; Link; Measures; Mediating; Microvascular Dysfunction; Mus; NADPH Oxidase; Outcome; Oxidative Stress; Plasma; Preparation; Production; Rattus; Reactive Oxygen Species; Receptor Activation; Regulation; Renal Blood Flow; Renal function; Reperfusion Injury; Reperfusion Therapy; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Sphingolipids; Sphingosine-1-Phosphate Receptor; Superoxide Dismutase; Survivors; Techniques; Testing; Tissues; Tubular formation; Ultrasonics; Work; arteriole; edg-1 Protein; effective therapy; hemodynamics; improved; in vivo; insight; mimetics; mortality; new therapeutic target; novel; prevent; protein expression; receptor expression; renal ischemia; response; sphingosine 1-phosphate; sphingosine kinase; tempol; vasoconstriction; virtual; xanthine oxidase inhibitor

Renal ischemia-reperfusion (IR) is a leading cause of acute kidney injury (IR-AKI), a significant unsolved clinical problem. A critical barrier to progress with IR-AKI is that there are gaps in our scientific understanding of the mechanisms underlying the persistent reduction of medullary blood flow (MBF), a key factor determining the outcome of IR-AKI and the progression to chronic kidney disease (CKD). Our goal is to address this critical barrier by focusing on the role of sphingosine-1-phosphate (S1P) as a potential signaling molecule contributing to renal microvascular dysfunction in IR-AKI. Our central hypothesis is that renal ischemia-reperfusion leads to significantly enhanced sensitivity of juxtamedullary afferent arterioles, the crucial vascular segment that controls MBF, to S1P-mediated vasoconstriction which contributes to a persistent reduction of MBF and a steady decline in glomerular filtration rate (GFR) in IR-AKI. Our objectives are to address this central hypothesis by (1) determining the role of S1P in controlling juxtamedullary afferent arteriolar function and renal hemodynamics in IR-AKI; (2) establishing the cellular mechanisms of S1P- dependent regulation of afferent arteriolar reactivity in IR-AKI; and (3) determining the pathophysiological role of S1P in the development of renal microvascular dysfunction in IR-AKI. We will test this central hypothesis through three specific aims. AIM 1 will test the hypothesis that renal ischemia-reperfusion leads to enhanced sensitivity of afferent arterioles to S1P which contributes to a persistent vasoconstriction and reduction of MBF in IR-AKI. AIM 2 will test the hypothesis that the renal ischemia-reperfusion-induced increase in reactive oxygen species production contributes to enhanced S1P sensitivity of afferent arterioles in IR-AKI. AIM 3 will test the hypothesis that inhibition of S1P receptor activation prevents enhancement of S1P-mediated afferent arteriolar vasoconstriction during ischemia-reperfusion and protects against IR-AKI. We will use the in vitro blood-perfused juxtamedullary nephron technique to assess the impact of IR on S1P-mediated arteriolar response in rats and in S1P2 receptor knockout mice. We will determine the influence of S1P on total and regional renal blood flow and GFR with IR-AKI. We will determine which S1P receptors contribute to enhanced S1P-mediated vasoconstriction. We will measure sphingolipid metabolites in kidney and plasma of IR rats or mice. Our outcomes will provide new mechanistic insights that renal IR activates the S1P signaling pathway in the renal microvasculature. Exogenous S1P causes potent vasoconstriction of afferent arterioles and reduction of renal blood flow and MBF, which will be enhanced in IR-AKI. S1P2 receptor blockade or deletion will protect against IR-AKI. The results of this study will improve our understanding of the pathophysiological mechanisms underlying the persistent reduction of MBF and a steady decline in GFR in IR-AKI. Improving MBF by inhibiting S1P2R signaling may represent a new therapeutic target for treating IR-AKI and preventing progression to CKD, thereby having a major impact in the field.

肾缺血-再灌注（IR）是急性肾损伤（IR-AKI）的主要原因，这是一个重要的未解决的问题。 临床问题IR-AKI进展的一个关键障碍是我们的科学研究存在差距， 了解髓血流量持续减少（MBF）的机制，是一个关键 决定IR-AKI结局和进展为慢性肾病（CKD）的因素。我们的目标是 通过关注鞘氨醇-1-磷酸（S1 P）作为潜在信号传导的作用， IR-AKI中导致肾微血管功能障碍的分子。我们的中心假设是， 缺血-再灌注导致延髓传入小动脉的敏感性显著增强， 控制MBF的血管段，S1 P介导的血管收缩，这有助于持续的 在IR-AKI中，MBF降低和肾小球滤过率（GFR）稳定下降。我们的目标为 通过（1）确定S1 P在控制延髓传入神经中的作用， （2）建立S1 P-1在IR-AKI中的细胞机制; IR-AKI中传入小动脉反应性的依赖性调节;以及（3）确定病理生理学作用 S1 P在IR-AKI中肾微血管功能障碍的发展中的作用。我们将检验这一中心假设 通过三个具体目标。目的1将检验肾缺血再灌注导致增强的 传入小动脉对S1 P的敏感性，这有助于持续的血管收缩和MBF的减少 在IR-AKI。目的2将验证肾缺血再灌注诱导的反应性增加的假设， 氧物质产生有助于IR-AKI中传入小动脉的S1 P敏感性增强。AIM 3将 测试抑制S1 P受体激活阻止S1 P介导的传入增强的假设 在缺血-再灌注过程中的小动脉血管收缩和保护免受IR-AKI。我们将使用体外 血液灌注延髓肾单位技术评估IR对S1 P介导的小动脉的影响 大鼠和S1 P2受体敲除小鼠的反应。我们将确定S1 P对总体的影响， IR-AKI患者的局部肾血流量和GFR。我们将确定哪些S1 P受体有助于增强 S1 P介导的血管收缩。我们将测量IR大鼠的肾脏和血浆中的鞘脂代谢物， 小鼠我们的结果将提供新的机制的见解，肾IR激活S1 P信号通路 在肾脏微血管中。外源性S1 P引起传入小动脉的有效血管收缩， 肾血流量和MBF减少，这将在IR-AKI中增强。S1 P2受体阻断或缺失 将防止IR-AKI。这项研究的结果将提高我们对病理生理学的理解， IR-AKI中MBF持续降低和GFR稳定下降的潜在机制。改善 通过抑制S1 P2 R信号传导的MBF可能代表用于治疗IR-AKI和预防IR-AKI的新的治疗靶点。 进展为CKD，从而在该领域产生重大影响。