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Enhanced Expression and Function of Renal SGLT2 (Sodium-Glucose Cotransporter 2) in Heart Failure: Role of Renal Nerves
Circulation: Heart Failure ( IF 9.7 ) Pub Date : 2021-11-18 , DOI: 10.1161/circheartfailure.121.008365
Kenichi Katsurada 1 , Shyam S Nandi 1 , Neeru M Sharma 1 , Kaushik P Patel 1
Affiliation  

Background:Recent clinical studies demonstrate that SGLT2 (sodium-glucose cotransporter 2) inhibitors ameliorate heart failure (HF). The present study was conducted to assess the expression and function of renal SGLT2 and the influence of enhanced renal sympathetic tone in HF.Methods:Four weeks after coronary artery ligation surgery to induce HF, surgical bilateral renal denervation (RDN) was performed in rats. Four groups of rats (Sham-operated control [Sham], Sham+RDN, HF and HF+RDN; n=6/group) were used. Immunohistochemistry and Western blot analysis were performed to evaluate the renal SGLT2 expression. One week after RDN (5 weeks after induction of HF), intravenous injection of SGLT2 inhibitor dapagliflozin were performed to assess renal excretory responses. In vitro, human embryonic kidney cells were used to investigate the fractionation of SGLT2 after norepinephrine treatment.Results:In rats with HF, (1) SGLT2 expression in the proximal tubule of the kidney was increased; (2) the response of increases in urine flow, sodium excretion, and glucose excretion to dapagliflozin were greater; and (3) RDN attenuated renal SGLT2 expression and normalized renal functional responses to dapagliflozin. In vitro, norepinephrine promoted translocation of SGLT2 to the cell membrane.Conclusions:These results indicate that the enhanced tonic renal sympathetic nerve activation in HF increases the expression and functional activity of renal SGLT2. Potentiated trafficking of SGLT2 to cell surface in renal proximal tubules mediated by norepinephrine may contribute to this functional activation of SGLT2 in HF. These findings provide critical insight into the underlying mechanisms for the beneficial effects of SGLT2 inhibitors on HF reported in the clinical studies.

中文翻译:

增强肾 SGLT2(钠-葡萄糖协同转运蛋白 2)在心力衰竭中的表达和功能:肾神经的作用

背景:最近的临床研究表明,SGLT2(钠-葡萄糖协同转运蛋白 2)抑制剂可改善心力衰竭 (HF)。本研究旨在评估肾脏 SGLT2 的表达和功能以及肾交感神经张力增强对 HF 的影响。方法:冠状动脉结扎手术诱导 HF 后 4 周,对大鼠进行手术双侧肾去神经支配 (RDN)。使用四组大鼠(假手术对照[假手术]、假手术+RDN、HF和HF+RDN;n=6/组)。进行免疫组织化学和蛋白质印迹分析以评估肾 SGLT2 表达。RDN 后 1 周(诱导 HF 后 5 周),静脉注射 SGLT2 抑制剂达格列净以评估肾脏排泄反应。体外,采用人胚肾细胞研究去甲肾上腺素治疗后SGLT2的分离。(2)尿流量增加、钠排泄和葡萄糖排泄增加对达格列净的反应更大;(3) RDN 减弱肾 SGLT2 表达并使肾功能对达格列净的反应正常化。在体外,去甲肾上腺素促进 SGLT2 向细胞膜的易位。结论:这些结果表明,HF 中增强的肾交感神经激活增强增强了肾 SGLT2 的表达和功能活性。由去甲肾上腺素介导的 SGLT2 向肾近端小管细胞表面的增强运输可能有助于 HF 中 SGLT2 的这种功能激活。
更新日期:2021-12-22
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