Novel target mechanism (renal nerves) for the beneficial actions of SGLT2 inhibition in congestive heart failure

SGLT2 抑制对充血性心力衰竭有益作用的新靶点机制（肾神经）

• 批准号: 10669642
• 负责人: KAUSHIK P PATEL
• 金额: $ 49.8万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669642
• 关键词: Address; Adrenergic Receptor; Animals; Attenuated; Canis familiaris; Cardiac; Cardiopulmonary; Cardiorenal syndrome; Cells; Chronic; Clinical; Clinical Research; Congestive Heart Failure; Data; Denervation; Disease Progression; Dyspnea; Edema; Electrophysiology (science); Equilibrium; Event; Excretory function; Fatigue; Feedback; Functional disorder; Glucose; Heart failure; Hospitalization; Hyponatremia; Impairment; Inflammation; Inflammatory; Kidney; Liquid substance; Measurement; Mediating; Methodology; Molecular; Molecular Biology Techniques; Nausea; Nerve; Norepinephrine; Organ; Patients; Physiological; Prognosis; Proximal Kidney Tubules; Rattus; Regulation; Renal function; Renal tubule structure; Risk; Sodium; Splanchnic Nerves; Symptoms; System; Testing; Therapeutic; Tubular formation; Type 2 diabetic; Water; absorption; cytokine; diabetic patient; heart function; hemodynamics; immune activation; immune cell infiltrate; inhibitor; insight; mortality; non-diabetic; novel; prevent; response; symporter; trafficking

Project Summary One hallmark feature of congestive heart failure (CHF) is sodium and fluid retention and in combination with neurohumoral activation leads to poor prognosis and high mortality. Sodium-glucose cotransporter 2 (SGLT2) is localized in the proximal convoluted tubule of the kidney and responsible for 90% of glucose reabsorption. Based on this fact SGLT2 inhibitors promoting glucose excretion are widely used to treat type 2 diabetic patients. To date, clinical studies suggest that SGLT2 inhibitors suppress the risk for hospitalization and mortality for heart failure in type 2 diabetic patients. Further, in non-diabetic patients with CHF, SGLT2 inhibitor prevents worsening heart failure and mortality. Multiple mechanisms have been proposed to be involved in the beneficial effects of SGLT2 inhibitors in CHF. Renal sympathetic nerve activation causes sodium and water retention in CHF. Renal denervation (RDN) has been shown to reduce sodium retention in rats and dogs with CHF. Activation of the splanchnic sympathetic nerve leads to volume redistribution such as to contribute to cardiopulmonary congestion in CHF. Our recent evidence in rats with CHF shows that; 1) levels of SGLT2 expression are dramatically increased in the proximal tubules of the kidney; 2) the activity of SGLT2 for sodium retention is enhanced; 3) RDN decreases the levels of SGLT2 expression and SGLT2 activity; 4) norepinephrine upregulates SGLT2 expression and trafficking in the renal tubular cells; and 5) RDN attenuates renal levels of inflammatory cytokines and renal immune cell activation. Based on these data, we will test the hypothesis that elevated sympathetic activation in CHF enhances sodium reabsorption and fluid retention by modulation of SGLT2 expression, trafficking and function. Further, enhanced SGLT2 expression potentiates a vicious positive feedback between renal inflammation and increases in sympathetic activation (both renal and splanchnic nerves) in CHF. In AIM 1 we will determine if enhanced expression/activation of renal SGLT2 contributes to the sodium retention in rats with CHF. In AIM 2 we will determine if RDN or selective afferent renal denervation abrogates the expression/activation of SGLT2, possibly via renal inflammation in rats with CHF. In Aim 3 we will determine if SGLT2 inhibition reduces efferent/afferent renal and splanchnic sympathetic activation in rats with CHF. These aims will be addressed in rats with CHF using complementary methodologies ranging from cellular to the whole animal level, including physiological measurement of sodium balance, volume status, SGLT2 activity, electrophysiological recording, SGLT2 trafficking using molecular biology techniques. The successful completion of the proposed studies will provide significant new information and insight into the contribution of SGLT2 inhibition on renal nerve mediated regulation in altered sodium balance in CHF and the therapeutic benefits of SGLT2 mediated changes in renal nerve mediated sodium and fluid retention, endemic to CHF.

项目摘要 充血性心力衰竭（CHF）的一个标志性特征是钠和液体保留，并与 神经肿瘤激活导致预后不良和高死亡率。钠 - 葡萄糖共转运蛋白2（SGLT2）为 位于肾脏的近端复杂小管中，并导致90％的葡萄糖重吸收。基于 因此，SGLT2抑制剂促进葡萄糖排泄被广泛用于治疗2型糖尿病患者。到 日期，临床研究表明SGLT2抑制剂抑制了心脏住院和死亡率的风险 2型糖尿病患者的失败。此外，在非糖尿病患者中，SGLT2抑制剂可防止恶化 心力衰竭和死亡率。已经提出多种机制参与 CHF中的SGLT2抑制剂。肾交感神经激活会导致CHF的钠和水分retention留。肾脏 已证明去神经（RDN）可减少大鼠和有CHF的狗的钠。激活 神经交感神经会导致体积重新分布，例如为心肺充血做出贡献 在瑞士法郎。我们最近在CHF大鼠中的证据表明； 1）SGLT2表达的水平急剧 肾脏近端小管的增加； 2）SGLT2用于钠保留的活性得到了增强； 3） RDN降低了SGLT2表达和SGLT2活性的水平。 4）去甲肾上腺素上调SGLT2 肾小管细胞中的表达和运输； 5）RDN减弱肾脏炎性细胞因子的水平 和肾脏免疫细胞激活。基于这些数据，我们将检验以下假设： CHF激活通过调节SGLT2表达，增强钠的吸收和液体保留， 贩运和功能。此外，增强的SGLT2表达式增强了恶性积极反馈 肾脏炎症和交感神经激活的增加（肾脏和闪烁神经）之间 在瑞士法郎。在AIM 1中，我们将确定肾脏SGLT2的表达/激活是否有助于钠 保留在CHF​​的大鼠中。在AIM 2中，我们将确定RDN或选择性传入的肾脏神经膜是否废除 SGLT2的表达/激活，可能是通过CHF大鼠的肾脏炎症。在AIM 3中，我们将确定 如果SGLT2抑制作用可减少CHF大鼠的传出/传入肾脏和斑点交感神经激活。这些 目的将在CHF中使用从细胞到整体的互补方法来解决大鼠。 动物水平，包括钠平衡，体积状态，SGLT2活性的生理测量， 电生理记录，使用分子生物学技术的SGLT2运输。成功完成 在拟议的研究中，将为SGLT2的贡献提供重要的新信息和见解 抑制CHF改变钠平衡改变的肾神经介导调节和治疗益处 SGLT2介导的肾神经介导的钠和液体保留的变化，是CHF特有的。