Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect.
Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect.
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DOI：
10.1038/s41419-018-0273-y
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发表时间：
2018-02-14
影响因子：
9
通讯作者：
Dietrich DR
中科院分区：
文献类型：
--
作者：
Secker PF;Beneke S;Schlichenmaier N;Delp J;Gutbier S;Leist M;Dietrich DR
最近的FDA药物安全性通讯报告称，在接受适用于治疗2型糖尿病的神经胶质瘤类钠/葡萄糖共转运抑制剂治疗的患者中，急性肾损伤的风险增加。为了确定后者的潜在原理，我们使用了体外人肾近端小管上皮细胞模型系统（RPTEC/TERT 1），生理上代表人肾近端小管功能。一种靶向代谢组学方法，将格列净与中心碳代谢和线粒体功能抑制剂进行对比，揭示了卡格列净的双重作用模式，但其类似物达格列净和恩格列净并非如此。在临床相关浓度下，卡格列净可抑制谷氨酸脱氢酶（GDH）和线粒体电子传递链（ETC）复合物I。这种双重抑制特异性地阻止了谷氨酰胺对三羧酸循环代谢物的补充（回补），从而通过增加代偿性转氨反应改变了氨基酸库。因此，卡格列净导致谷氨酰胺、谷氨酸和丙氨酸在融合、静止的RPTEC/TERT 1中发生特征性细胞内蓄积。卡格列净（但不是经典ETC抑制剂）在增殖的RPTEC/TERT 1中以特别低的浓度诱导细胞毒性，用作原位近端小管再生的模型。这一发现证明了增殖细胞对通过GDH的谷氨酰胺回补的强烈依赖性。我们发现，在临床相关浓度下，卡格列净介导的肾细胞中GDH和ETC复合物I的同时抑制，以及它们在增殖期间对坏死细胞死亡的特殊易感性，为观察到的不良反应提供了机制依据，尤其是在既存慢性肾病或既往肾损伤（特征为持续再生肾小管上皮细胞增殖）患者中。
Recent FDA Drug Safety Communications report an increased risk for acute kidney injury in patients treated with the gliflozin class of sodium/glucose co-transport inhibitors indicated for treatment of type 2 diabetes mellitus. To identify a potential rationale for the latter, we used an in vitro human renal proximal tubule epithelial cell model system (RPTEC/TERT1), physiologically representing human renal proximal tubule function. A targeted metabolomics approach, contrasting gliflozins to inhibitors of central carbon metabolism and mitochondrial function, revealed a double mode of action for canagliflozin, but not for its analogs dapagliflozin and empagliflozin. Canagliflozin inhibited the glutamate dehydrogenase (GDH) and mitochondrial electron transport chain (ETC) complex I at clinically relevant concentrations. This dual inhibition specifically prevented replenishment of tricarboxylic acid cycle metabolites by glutamine (anaplerosis) and thus altered amino acid pools by increasing compensatory transamination reactions. Consequently, canagliflozin caused a characteristic intracellular accumulation of glutamine, glutamate and alanine in confluent, quiescent RPTEC/TERT1. Canagliflozin, but none of the classical ETC inhibitors, induced cytotoxicity at particularly low concentrations in proliferating RPTEC/TERT1, serving as model for proximal tubule regeneration in situ. This finding is testimony of the strong dependence of proliferating cells on glutamine anaplerosis via GDH. Our discovery of canagliflozin-mediated simultaneous inhibition of GDH and ETC complex I in renal cells at clinically relevant concentrations, and their particular susceptibility to necrotic cell death during proliferation, provides a mechanistic rationale for the adverse effects observed especially in patients with preexisting chronic kidney disease or previous kidney injury characterized by sustained regenerative tubular epithelial cell proliferation.
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影响因子：
5.3
作者：
Aschauer, Lydia;Gruber, Leonhard N.;Jennings, Paul
通讯作者：
Jennings, Paul
影响因子：
--
作者：
DICKMAN, KG;MANDEL, LJ
通讯作者：
MANDEL, LJ
影响因子：
2.9
作者：
Devineni, Damayanthi;Curtin, Christopher R.;Rothenberg, Paul L.
通讯作者：
Rothenberg, Paul L.
DOI：
10.1007/bf01542645
发表时间：
1979-01-01
期刊：
SOMATIC CELL GENETICS
影响因子：
--
作者：
HOWELL, N;SAGER, R
通讯作者：
SAGER, R
DOI：
10.1073/pnas.1316177111
发表时间：
2014-01-28
影响因子：
11.1
作者：
Berger, Katja;Bangen, Joerg-Martin;Moeller, Marcus Johannes
通讯作者：
Moeller, Marcus Johannes