最新进展回顾 SGLT2 抑制剂的作用机制和临床意义。

IF 3.2 3区 医学 Q2 PERIPHERAL VASCULAR DISEASE
Volker Vallon
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引用次数: 0

摘要

Na+ 偶联葡萄糖转运体 SGLT2(SGLT2i)的抑制剂主要是将大量葡萄糖的重吸收从肾脏早期近端肾小管转移到下游表达 SGLT1 的肾小管节段,未被重吸收的葡萄糖在渗透性利尿的同时溢出到尿液中。这如何能保护肾脏和心脏,避免在 2 型糖尿病患者和非 2 型糖尿病患者身上观察到的衰竭?中介分析确定了 SGLT2i 与改善肾脏和心脏预后相关的临床表型,包括减少血浆容量或增加血细胞比容、降低血清尿酸水平和白蛋白尿。本综述概述了 SGLT2i 对早期近端肾小管的主要影响如何解释这些表型。肾小管与肾小球之间的生理学交流为急性降低肾小球滤过率和肾小球毛细血管压力提供了基础,这不仅有助于降低白蛋白尿,还能长期维持肾小球滤过率,至少部分原因是通过降低肾皮质的需氧量。SGLT2 与早期近端肾小管中的其他钠和代谢物转运体在功能上共同调控,这就解释了为什么 SGLT2i 最初排出的钠比预期的要多,而且具有尿酸尿作用,从而减少了血浆容量和血清尿酸盐。抑制 SGLT2 可降低早期近端肾小管的葡萄糖毒性,并通过向下游转运可模拟 "全身缺氧",从而增加红细胞生成,加上渗透性利尿,可提高血细胞比容,改善血氧输送。SGLT2i 还能通过类似禁食和节省胰岛素的代谢表型,以及对心脏和尿毒症毒素微生物形成的脱靶效应,提供心肾保护。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
State-of-the-Art-Review: Mechanisms of Action of SGLT2 Inhibitors and Clinical Implications.

Background: Inhibitors of the Na+-coupled glucose transporter SGLT2 (SGLT2i) primarily shift the reabsorption of large amounts of glucose from the kidney's early proximal tubule to downstream tubular segments expressing SGLT1, and the non-reabsorbed glucose is spilled into the urine together with some osmotic diuresis. How can this protect the kidneys and heart from failing as observed in individuals with and without type 2 diabetes?

Goal: Mediation analyses identified clinical phenotypes of SGLT2i associated with improved kidney and heart outcome, including a reduction of plasma volume or increase in hematocrit, and lowering of serum urate levels and albuminuria. This review outlines how primary effects of SGLT2i on the early proximal tubule can explain these phenotypes.

Results: The physiology of tubule-glomerular communication provides the basis for acute lowering of GFR and glomerular capillary pressure, which contributes to lowering of albuminuria but also to long term preservation of GFR, at least in part by reducing kidney cortex oxygen demand. Functional co-regulation of SGLT2 with other sodium and metabolite transporters in the early proximal tubule explains why SGLT2i initially excrete more sodium than expected and are uricosuric, thereby reducing plasma volume and serum urate. Inhibition of SGLT2 reduces early proximal tubule gluco-toxicity and by shifting transport downstream may simulate "systemic hypoxia", and the resulting increase in erythropoiesis, together with the osmotic diuresis, enhances hematocrit and improves blood oxygen delivery. Cardio-renal protection by SGLT2i is also provided by a fasting-like and insulin-sparing metabolic phenotype and, potentially, by off-target effects on the heart and microbiotic formation of uremic toxins.

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来源期刊
American Journal of Hypertension
American Journal of Hypertension 医学-外周血管病
CiteScore
6.90
自引率
6.20%
发文量
144
审稿时长
3-8 weeks
期刊介绍: The American Journal of Hypertension is a monthly, peer-reviewed journal that provides a forum for scientific inquiry of the highest standards in the field of hypertension and related cardiovascular disease. The journal publishes high-quality original research and review articles on basic sciences, molecular biology, clinical and experimental hypertension, cardiology, epidemiology, pediatric hypertension, endocrinology, neurophysiology, and nephrology.
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