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）的一个标志性特征是钠和液体潴留， 神经体液激活导致不良预后和高死亡率。钠-葡萄糖协同转运蛋白2（SGLT 2）是 其位于肾脏的近曲小管中并负责90%的葡萄糖重吸收。基于 基于这一事实，促进葡萄糖排泄的SGLT 2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，SGLT 2抑制剂可抑制心脏病住院和死亡的风险 2型糖尿病患者中的失败。此外，在非糖尿病CHF患者中，SGLT 2抑制剂可预防恶化 心力衰竭和死亡率。已经提出了多种机制参与的有益效果 CHF中的SGLT 2抑制剂。肾交感神经激活导致CHF中的钠和水潴留。肾 去神经支配（RDN）已显示减少患有CHF的大鼠和狗中的钠潴留。激活 内脏交感神经导致容量重新分布， 单位：瑞士法郎。我们最近在CHF大鼠中的证据表明：1）SGLT 2表达水平显著升高， 在肾脏近端小管中增加; 2）SGLT 2的钠潴留活性增强; 3） RDN降低SGLT 2表达水平和SGLT 2活性; 4）去甲肾上腺素上调SGLT 2 表达和运输的肾小管细胞;和5）RDN减弱肾水平的炎性细胞因子 和肾免疫细胞活化。基于这些数据，我们将检验交感神经水平升高 CHF中的激活通过调节SGLT 2表达增强钠重吸收和液体潴留， 贩运和功能。此外，SGLT 2表达增强可增强恶性正反馈 肾脏炎症与交感神经激活增加（肾神经和内脏神经）之间的关系 单位：瑞士法郎。在AIM 1中，我们将确定肾脏SGLT 2的表达/活化增强是否有助于钠代谢。 CHF大鼠的潴留。在AIM 2中，我们将确定是否RDN或选择性传入肾去神经废除 SGLT 2的表达/激活，可能通过CHF大鼠的肾脏炎症。在目标3中，我们将确定 如果SGLT 2抑制可减少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CHF大鼠中解决目标 动物水平，包括钠平衡、容量状态、SGLT 2活性的生理测量， 电生理记录，使用分子生物学技术的SGLT 2运输。圆满完成 这些研究将为SGLT 2的贡献提供重要的新信息和见解 抑制肾神经介导的CHF钠平衡改变的调节以及 SGLT 2介导的肾神经介导的钠和液体潴留（CHF特有）的变化。

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.