SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition
SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition
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DOI：
10.1016/j.cmet.2020.06.020
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发表时间：
2020-09-01
期刊：
影响因子：
29
通讯作者：
Maegawa, Hiroshi
中科院分区：
文献类型：
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作者：
Tomita, Issei;Kume, Shinji;Maegawa, Hiroshi
SGLT2抑制剂在糖尿病肾病(DKD)患者中提供了强大的肾脏保护作用。但这种保护的机制尚不清楚。在这里，我们报道了在高脂饮食喂养的ApoE基因敲除小鼠(一种非蛋白尿性DKD模型)受损的近端小管中，由于雷帕霉素复合体1的机械靶(MTORC1)的过度激活，ATP的产生从脂解转变为酮解依赖。我们进一步发现，empagliflzin提高了内源性酮体(KB)的水平，因此它的使用或与KB前体1，3-丁二醇的治疗可以防止小鼠肾脏ATP水平的下降和器官损伤。酮体生成限速酶HMGCS2基因缺失取消了依帕格列酮的肾脏保护作用。此外，KBS可减轻糖尿病db/db小鼠mTORC1相关的足细胞损伤和蛋白尿。我们的发现表明，SGLT2抑制相关的肾脏保护是通过KBS的升高而介导的，KBS的升高反过来纠正了非蛋白尿性和蛋白尿性DKD中发生的mTORC1过度激活。
SGLT2 inhibitors offer strong renoprotection in subjects with diabetic kidney disease (DKD). But the mechanism for such protection is not clear. Here, we report that in damaged proximal tubules of high-fat diet-fed ApoE-knockout mice, a model of non-proteinuric DKD, ATP production shifted from lipolysis to ketolysis dependent due to hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). We further found that empagliflozin raised endogenous ketone body (KB) levels, and thus its use or treatment with 1,3-butanediol, a KB precursor, prevented decreases in renal ATP levels and organ damage in the mice. The renoprotective effect of empagliflozin was abolished by gene deletion of Hmgcs2, a rate-limiting enzyme of ketogenesis. Furthermore, KBs attenuated mTORC1-associated podocyte damage and proteinuria in diabetic db/db mice. Our findings show that SGLT2 inhibition-associated renoprotection is mediated by an elevation of KBs that in turn corrects mTORC1 hyperactivation that occurs in non-proteinuric and proteinuric DKD.