Inhibition of glycogen synthase kinase-3β prevents NSAID-induced acute kidney injury.
Inhibition of glycogen synthase kinase-3β prevents NSAID-induced acute kidney injury.
复制标题
抑制糖原合酶激酶-3β可以防止NSAID诱导的急性肾脏损伤。
DOI：
10.1038/ki.2011.443
复制
发表时间：
2012-04
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
作者：
双氯芬酸（DCLF）等非甾体抗炎药（NSAID）的临床使用受到多种不良反应的限制，包括导致急性肾损伤的肾毒性。在DCLF诱导的肾毒性小鼠中，选择性糖原合成酶激酶（GSK）3β抑制剂TDZD-8改善了急性肾功能障碍，改善了与诱导的皮质环氧合酶-2（考克斯-2）和前列腺素E2表达相关的肾小管坏死和细胞凋亡。这种肾脏保护作用减弱，但在考克斯-2敲除小鼠中仍在很大程度上得以保留，这表明考克斯-2以外的其他GSK 3 β靶点在肾脏保护中发挥作用。事实上，TDZD-8减少了DCLF损伤的肾脏中的线粒体渗透性转变。在体外，GSK 3 β抑制恢复活力，并抑制DCLF刺激的肾小管上皮细胞的坏死和凋亡。DCLF引起氧化应激，增强氧化还原敏感性GSK 3 β的活性，并通过与线粒体渗透性转换孔的关键组分亲环素D相互作用促进线粒体渗透性转换。TDZD-8阻断GSK 3 β活性，阻止GSK 3 β介导的亲环蛋白D磷酸化和随后的线粒体通透性转变，伴随着细胞内ATP的正常化。相反，组成性活性GSK 3 β的异位表达消除了TDZD-8的作用。因此，抑制GSK 3 β可通过诱导肾皮质考克斯-2和直接抑制线粒体通透性转换来改善NSAID诱导的急性肾损伤。
Clinical use of non-steroidal anti-inflammatory drugs (NSAIDs) like diclofenac (DCLF) is limited by multiple adverse effects, including renal toxicity leading to acute kidney injury. In mice with DCLF-induced nephrotoxicity TDZD-8, a selective glycogen synthase kinase (GSK)3β inhibitor, improved acute kidney dysfunction, ameliorated tubular necrosis and apoptosis associated with induced cortical expression of cyclooxygenase-2 (COX-2) and prostaglandin E2. This renoprotective effect was blunted but still largely preserved in COX-2 null mice, suggesting that other GSK3β targets beyond COX-2 functioned in renal protection. Indeed, TDZD-8 diminished the mitochondrial permeability transition in DCLF-injured kidneys. In vitro, GSK3β inhibition reinstated viability and suppressed necrosis and apoptosis in DCLF-stimulated tubular epithelial cells. DCLF elicited oxidative stress, enhanced the activity of the redox-sensitive GSK3β and promoted a mitochondrial permeability transition by interacting with cyclophilin D, a key component of the mitochondrial permeability transition pore. TDZD-8 blocked GSK3β activity, prevented GSK3β mediated cyclophilin D phosphorylation and the ensuing mitochondrial permeability transition, concomitant with normalization of intracellular ATP. Conversely, ectopic expression of a constitutively active GSK3β abolished the effects of TDZD-8. Hence, inhibition of GSK3β ameliorates NSAID-induced acute kidney injury by induction of renal cortical COX-2 and direct inhibition of the mitochondrial permeability transition.
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DOI：
10.1152/ajprenal.00114.2004
发表时间：
2005-05-01
影响因子：
4.2
作者：
Kotnik, P;Nielsen, J;Nielsen, S
通讯作者：
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影响因子：
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作者：
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发表时间：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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