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）

基本信息

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
项目类别：
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

项目摘要

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.

项目概要充血性心力衰竭 (CHF) 的标志之一是钠和液体潴留，并与神经体液激活导致预后不良和死亡率高。钠-葡萄糖协同转运蛋白 2 (SGLT2) 是位于肾近曲小管，负责 90% 的葡萄糖重吸收。基于鉴于此，促进葡萄糖排泄的SGLT2抑制剂被广泛用于治疗2型糖尿病患者。到迄今为止，临床研究表明 SGLT2 抑制剂可抑制心脏病住院和死亡的风险 2型糖尿病患者失败。此外，在患有 CHF 的非糖尿病患者中，SGLT2 抑制剂可防止病情恶化心力衰竭和死亡率。已提出多种机制参与其有益效果 CHF 中的 SGLT2 抑制剂。肾交感神经激活导致 CHF 中钠和水潴留。肾去神经支配 (RDN) 已被证明可以减少患有 CHF 的大鼠和狗的钠潴留。激活内脏交感神经导致容量重新分配，从而导致心肺充血单位为瑞士法郎。我们最近在慢性心力衰竭大鼠身上的证据表明： 1) SGLT2 表达水平显着升高肾近端小管增加; 2) SGLT2钠潴留活性增强； 3） RDN 降低 SGLT2 表达水平和 SGLT2 活性； 4) 去甲肾上腺素上调SGLT2 肾小管细胞的表达和运输； 5) RDN 降低肾脏炎症细胞因子水平和肾脏免疫细胞激活。根据这些数据，我们将检验以下假设：交感神经增强 CHF 中的激活通过调节 SGLT2 表达增强钠重吸收和液体潴留，贩运和功能。此外，增强的 SGLT2 表达会增强恶性正反馈肾脏炎症和交感神经激活增加（肾神经和内脏神经）之间的关系单位为瑞士法郎。在 AIM 1 中，我们将确定肾 SGLT2 表达/激活的增强是否有助于钠 CHF 大鼠的滞留。在 AIM 2 中，我们将确定 RDN 或选择性传入肾去神经术是否会废除 SGLT2 的表达/激活，可能通过 CHF 大鼠的肾脏炎症来实现。在目标 3 中，我们将确定如果 SGLT2 抑制减少 CHF 大鼠的传出/传入肾和内脏交感神经激活。这些将使用从细胞到整体的补充方法在患有 CHF 的大鼠中实现目标动物水平，包括钠平衡的生理测量、容量状态、SGLT2 活性、电生理记录，使用分子生物学技术进行 SGLT2 运输。顺利完成拟议的研究将为 SGLT2 的贡献提供重要的新信息和见解抑制肾神经介导的 CHF 钠平衡改变的调节及其治疗益处 SGLT2 介导肾神经介导的钠和液体潴留的变化，这是 CHF 特有的。