BACKGROUND:SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood.METHODS:To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improvement by SGLT2i, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis by integrating signatures from multiple metabolic organs and body fluids after 1 week of SGLT2i treatment of nondiabetic as well as diabetic mice with early and uncomplicated hyperglycemia.RESULTS:Kidneys of nondiabetic mice reacted most strongly to SGLT2i in terms of proteomic reconfiguration, including evidence for less early proximal tubule glucotoxicity and a broad downregulation of the apical uptake transport machinery (including sodium, glucose, urate, purine bases, and amino acids), supported by mouse and human SGLT2 interactome studies. SGLT2i affected heart and liver signaling, but more reactive organs included the white adipose tissue, showing more lipolysis, and, particularly, the gut microbiome, with a lower relative abundance of bacteria taxa capable of fermenting phenylalanine and tryptophan to cardiovascular uremic toxins, resulting in lower plasma levels of these compounds (including p-cresol sulfate). SGLT2i was detectable in murine stool samples and its addition to human stool microbiota fermentation recapitulated some murine microbiome findings, suggesting direct inhibition of fermentation of aromatic amino acids and tryptophan. In mice lacking SGLT2 and in patients with decompensated heart failure or diabetes, the SGLT2i likewise reduced circulating p-cresol sulfate, and p-cresol impaired contractility and rhythm in human induced pluripotent stem cell–derived engineered heart tissue.CONCLUSIONS:SGLT2i reduced microbiome formation of uremic toxins such as p-cresol sulfate and thereby their body exposure and need for renal detoxification, which, combined with direct kidney effects of SGLT2i, including less proximal tubule glucotoxicity and a broad downregulation of apical transporters (including sodium, amino acid, and urate uptake), provides a metabolic foundation for kidney and cardiovascular protection.

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SGLT2 抑制的代谢通讯

背景：SGLT2（钠-葡萄糖协同转运蛋白 2）抑制剂 (SGLT2i) 可以保护肾脏和心脏，但其潜在机制仍知之甚少。 方法：深入了解 SGLT2i 的主要作用，这些作用不会与病理生理过程混淆或继发于病理生理过程。通过 SGLT2i 的改进，我们对患有早期和无并发症高血糖的非糖尿病和糖尿病小鼠进行 SGLT2i 治疗 1 周后，通过整合多个代谢器官和体液的特征，进行了深入的蛋白质组学、磷酸化蛋白质组学和代谢组学分析。非糖尿病小鼠在蛋白质组重构方面对 SGLT2i 反应最强烈，包括早期近端小管糖毒性较小的证据以及顶端摄取转运机制（包括钠、葡萄糖、尿酸盐、嘌呤碱和氨基酸）的广泛下调，得到小鼠的支持和人类 SGLT2 相互作用组研究。SGLT2i影响心脏和肝脏信号传导，但反应性更强的器官包括白色脂肪组织，显示出更多的脂解作用，特别是肠道微生物组，其能够将苯丙氨酸和色氨酸发酵成心血管尿毒症毒素的细菌分类群的相对丰度较低，从而导致降低这些化合物（包括对甲酚硫酸盐）的血浆水平。在小鼠粪便样本中可检测到 SGLT2i，并将其添加到人类粪便微生物群发酵中，重现了一些小鼠微生物组的发现，表明对芳香氨基酸和色氨酸的发酵有直接抑制作用。在缺乏 SGLT2 的小鼠以及失代偿性心力衰竭或糖尿病患者中，SGLT2i 同样减少了循环对甲酚硫酸盐，并且对甲酚损害了人诱导多能干细胞衍生的工程心脏组织的收缩性和节律。结论：SGLT2i 减少了微生物组的形成尿毒症毒素如对甲酚硫酸盐的产生，从而导致它们的身体暴露和肾脏解毒的需要，这与 SGLT2i 的直接肾脏作用相结合，包括减少近端小管葡萄糖毒性和广泛下调顶端转运蛋白（包括钠、氨基酸和尿酸盐摄取），为肾脏和心血管保护提供代谢基础。