Université Côte d'Azur, CNRS, LP2M, Nice, France.
CHU Nice, Hôpital Pasteur 2, Service de Réanimation Polyvalente et Service de Réanimation des Urgences Vitales, Nice, France.
Cell Death Dis. 2021 Mar 17;12(4):283. doi: 10.1038/s41419-021-03577-z.
Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin.
已证实，多胺类似物 GC7 抑制真核起始因子 5A 的激活，可保护近端细胞和整个肾脏免受急性缺血发作的影响。该突出机制涉及从氧化磷酸化到糖酵解的代谢转换，使细胞暂时不需要氧气供应。在这里，我们表明 GC7 降低了肾脏 GLUT1 葡萄糖转运蛋白的蛋白表达，导致细胞内葡萄糖通量降低。与此同时，GC7 将近端细胞的天然能量来源从谷氨酰胺改变为葡萄糖利用。因此，GC7 急性且可逆地重新编程了肾脏细胞的功能和代谢，使其仅使用葡萄糖作为单一底物，从而使细胞能够通过无氧糖酵解实现缺氧独立性。生理后果是肾脏葡萄糖和乳酸的排泄增加，反映了葡萄糖重吸收的减少和糖酵解的增加。GC7 对肾脏细胞葡萄糖处理和对氧气依赖性的这种可逆重编程代表了与缺血和高血糖相关的肾源性病理生理学中的一个药理学机会。
