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

项目摘要 充血性心力衰竭(CHF)的一个特点是钠和液体滞留，并与 神经体液激活导致预后不良，死亡率高。钠-葡萄糖共转运蛋白2(SGLT2)是 定位于肾脏近端曲管，负责90%的葡萄糖重吸收。基座 基于这一事实，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。至 临床研究表明，SGLT2抑制剂可降低心脏住院和死亡率的风险 2型糖尿病患者的失败。此外，在非糖尿病充血性心力衰竭患者中，SGLT2抑制剂可防止病情恶化 心力衰竭和死亡率。已有多个机制被提出涉及以下有益效果 SGLT2抑制剂在CHF中的应用。肾交感神经激活导致充血性心力衰竭时钠和水滞留。肾 去神经(RDN)已被证明可以减少充血性心力衰竭大鼠和狗的钠滞留。激活 内脏交感神经导致容量再分配，从而导致心肺充血 以瑞士法郎计算。我们最近在CHF大鼠身上的证据表明：1)SGLT2的表达水平显著 2)SGLT2的钠滞留活性增强；3) RDN降低SGLT2表达和SGLT2活性；4)去甲肾上腺素上调SGLT2 肾小管上皮细胞的表达和转运；5)RDN降低肾炎性细胞因子的水平 和肾脏免疫细胞的激活。基于这些数据，我们将检验提升交感神经的假设 CHF中的激活通过调节SGLT2的表达来增强钠的重吸收和液体滞留， 贩卖和行使职能。此外，增强的SGLT2表达加强了恶性的正反馈 肾脏炎症和交感神经激活(肾和内脏神经)增加之间的关系 以瑞士法郎计算。在目标1中，我们将确定肾脏SGLT2表达/激活增强是否与钠有关 充血性心力衰竭大鼠的滞留。在目标2中，我们将确定RDN或选择性传入肾神经切断是否可以废除 SGLT2的表达/激活可能通过慢性心力衰竭大鼠的肾脏炎症来实现。在目标3中，我们将确定 抑制SGLT2可降低CHF大鼠肾脏和内脏交感神经的传出/传出活性。这些 将使用从细胞到整体的补充方法来解决CHF大鼠的AIMS 动物水平，包括钠平衡、容量状态、SGLT2活性、 电生理记录，使用分子生物学技术进行SGLT2转运。圆满完成 将为SGLT2的贡献提供重要的新信息和洞察 慢性充血性心力衰竭钠平衡改变对肾神经调节的抑制作用及其治疗意义 SGLT2介导肾神经介导的钠和液体滞留的变化，这是CHF的地方性疾病。

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.