Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Department of Pharmacology, University of California San Diego, La Jolla, California, USA.
Am J Hypertens. 2024 Oct 14;37(11):841-852. doi: 10.1093/ajh/hpae092.
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.
钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂主要将大量葡萄糖的重吸收从肾脏早期近端小管转移到表达 SGLT1 的下游管状段，未被重吸收的葡萄糖与一些渗透性利尿一起溢出到尿液中。在患有和不患有 2 型糖尿病的个体中，这种情况如何保护肾脏和心脏免受衰竭？
中介分析确定了与改善肾脏和心脏结局相关的 SGLT2i 的临床表型，包括血浆体积减少或血细胞比容增加，以及血清尿酸水平和蛋白尿降低。本综述概述了 SGLT2i 对早期近端小管的主要作用如何解释这些表型。
管-球通讯的生理学为 GFR 和肾小球毛细血管压力的急性降低提供了基础，这有助于降低蛋白尿，但也有助于长期保留 GFR，至少部分原因是降低了肾脏皮质的氧气需求。早期近端小管中 SGLT2 与其他钠和代谢物转运体的功能协同调节解释了为什么 SGLT2i 最初排泄的钠比预期的多，并且具有尿酸排泄作用，从而减少了血浆体积和血清尿酸。SGLT2 的抑制减少了早期近端小管的葡萄糖毒性，并通过将转运物向下游转移，模拟“系统性缺氧”，从而增加红细胞生成，加上渗透性利尿，提高血细胞比容并改善血液氧输送。SGLT2i 对心脏和肾脏的保护还通过类似于禁食和胰岛素节约的代谢表型以及潜在的对心脏和微生物形成尿毒症毒素的非靶向作用提供。
