Sodium-glucose cotransporter 2 inhibitors reduce the risk of serious heart failure and adverse renal events, but the mechanisms that underlie this benefit are not understood. Treatment with SGLT2 inhibitors is distinguished by 2 intriguing features: ketogenesis and erythrocytosis. Both reflect the induction of a fasting-like and hypoxia-like transcriptional paradigm that is capable of restoring and maintaining cellular homeostasis and survival. In the face of perceived nutrient and oxygen deprivation, cells activate low-energy sensors, which include sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia inducible factors (HIFs; especially HIF-2α); these enzymes and transcription factors are master regulators of hundreds of genes and proteins that maintain cellular homeostasis. The activation of SIRT1 (through its effects to promote gluconeogenesis and fatty acid oxidation) drives ketogenesis, and working in concert with AMPK, it can directly inhibit inflammasome activation and maintain mitochondrial capacity and stability. HIFs act to promote oxygen delivery (by stimulating erythropoietin and erythrocytosis) and decrease oxygen consumption. The activation of SIRT1, AMPK, and HIF-2α enhances autophagy, a lysosome-dependent degradative pathway that removes dangerous constituents, particularly damaged mitochondria and peroxisomes, which are major sources of oxidative stress and triggers of cellular dysfunction and death. SIRT1 and AMPK also act on sodium transport mechanisms to reduce intracellular sodium concentrations. It is interesting that type 2 diabetes mellitus, obesity, chronic heart failure, and chronic kidney failure are characterized by the accumulation of intracellular glucose and lipid intermediates that are perceived by cells as indicators of energy overabundance. The cells respond by downregulating SIRT1, AMPK, and HIF-2α, thus leading to an impairment of autophagic flux and acceleration of cardiomyopathy and nephropathy. SGLT2 inhibitors reverse this maladaptive signaling by triggering a state of fasting and hypoxia mimicry, which includes activation of SIRT1, AMPK, and HIF-2α, enhanced autophagic flux, reduced cellular stress, decreased sodium influx into cells, and restoration of mitochondrial homeostasis. This mechanistic framework clarifies the findings of large-scale randomized trials and the close association of ketogenesis and erythrocytosis with the cardioprotective and renoprotective benefits of these drugs.

中文翻译：

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精神错乱的能量剥夺信号在感知营养过剩状态下心脏和肾脏疾病发病机制中的作用。

钠-葡萄糖协同转运蛋白 2 抑制剂可降低严重心力衰竭和不良肾脏事件的风险，但尚不清楚这种益处背后的机制。SGLT2 抑制剂治疗有两个有趣的特征：生酮和红细胞增多症。两者都反映了能够恢复和维持细胞稳态和存活的禁食样和缺氧样转录范式的诱导。面对感知到的营养和缺氧，细胞会激活低能量传感器，包括 Sirtuin-1 (SIRT1)、AMP 活化蛋白激酶 (AMPK) 和缺氧诱导因子 (HIFs；尤其是 HIF-2α)；这些酶和转录因子是数百种维持细胞稳态的基因和蛋白质的主要调节剂。SIRT1 的激活（通过其促进糖异生和脂肪酸氧化的作用）驱动生酮，并与 AMPK 协同工作，它可以直接抑制炎性体激活并维持线粒体容量和稳定性。HIF 的作用是促进氧气输送（通过刺激促红细胞生成素和红细胞增多症）并减少耗氧量。SIRT1、AMPK 和 HIF-2α 的激活增强了自噬，这是一种溶酶体依赖性降解途径，可去除危险成分，尤其是受损的线粒体和过氧化物酶体，它们是氧化应激的主要来源，也是细胞功能障碍和死亡的诱因。SIRT1 和 AMPK 还作用于钠转运机制以降低细胞内钠浓度。有趣的是，2 型糖尿病、肥胖症、慢性心力衰竭、和慢性肾功能衰竭的特征是细胞内葡萄糖和脂质中间体的积累，这些中间体被细胞视为能量过剩的指标。细胞通过下调 SIRT1、AMPK 和 HIF-2α 做出反应，从而导致自噬通量受损以及心肌病和肾病加速。SGLT2 抑制剂通过触发禁食和缺氧模拟状态来逆转这种适应不良的信号传导，包括激活 SIRT1、AMPK 和 HIF-2α，增强自噬通量，减少细胞应激，减少钠流入细胞，以及恢复线粒体稳态。这一机制框架阐明了大规模随机试验的结果，以及生酮和红细胞增多症与这些药物的心脏保护和肾脏保护益处之间的密切关联。