Abstract：
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? 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. 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.
摘要：
Na偶联葡萄糖转运蛋白SGLT2（SGLT2i）的抑制剂主要将大量葡萄糖从肾脏早期近端小管的重吸收转移到表达SGLT1的下游肾小管段，而未重吸收的葡萄糖与一些渗透性利尿一起溢出到尿液中。这如何保护肾脏和心脏免于在有和没有2型糖尿病的个体中观察到的衰竭？中介分析确定了与改善肾脏和心脏结果相关的SGLT2i的临床表型，包括血浆容量的减少或血细胞比容的增加，降低血清尿酸水平和蛋白尿。这篇综述概述了SGLT2i对早期近端小管的主要作用如何解释这些表型。肾小管-肾小球通讯的生理特性为急性降低GFR和肾小球毛细血管压提供了基础,这有助于降低白蛋白尿，但也有助于GFR的长期保存，至少部分是通过减少肾皮质的需氧量.SGLT2与早期近端小管中其他钠和代谢物转运蛋白的功能共调节解释了为什么SGLT2i最初排泄的钠比预期的多，并且是排尿的。从而减少血浆体积和血清尿酸。抑制SGLT2可降低早期近端小管的葡萄糖毒性，并通过向下游转移运输可模拟“全身性缺氧”，以及由此导致的红细胞生成增加，连同渗透性利尿，增强血细胞比容，改善血氧输送。SGLT2i的心肾保护还通过空腹样和胰岛素节约代谢表型提供，潜在的,通过对心脏和微生物形成尿毒症毒素的脱靶效应。
