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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：
10472675
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/10472675
关键词：
Address Adrenergic Receptor Animals Attenuated Canis familiaris Cardiac Cardiopulmonary Cells Chronic Clinical Clinical Research Congestive Congestive Heart Failure Data Denervation Disease Progression Dyspnea Edema Electrophysiology (science)Equilibrium Event Excretory function Fatigue Feedback Functional disorder Glucose Heart failure Hospitalization Hyponatremia Immune Impairment Infiltration 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 Syndrome System Testing Therapeutic Tubular formation Type 2 diabetic Water base cytokine diabetic patient heart function hemodynamics immune activation inhibitor insight mortality non-diabetic novel prevent response 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.

项目总结