Protective Effects of Cilastatin against Vancomycin-Induced Nephrotoxicity.
Protective Effects of Cilastatin against Vancomycin-Induced Nephrotoxicity.
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DOI：
10.1155/2015/704382
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发表时间：
2015
影响因子：
--
通讯作者：
Lázaro A
中科院分区：
文献类型：
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作者：
Humanes B;Jado JC;Camaño S;López-Parra V;Torres AM;Álvarez-Sala LA;Cercenado E;Tejedor A;Lázaro A
万古霉素是治疗严重感染的一种非常有效的抗生素。然而，其在临床实践中的使用受到肾毒性的限制。西司他丁是一种脱氢肽酶I抑制剂，作用于近端小管刷状缘膜，以防止亚胺培南蓄积和毒性。本研究旨在探讨西司他丁对万古霉素诱导的培养肾近端肾小管上皮细胞（RPTECs）凋亡和毒性的潜在保护作用。在万古霉素存在和不存在西司他丁的情况下培养猪RPTEC。万古霉素诱导培养的RPTECs剂量依赖性凋亡，DNA片段化，细胞脱落，线粒体活性显着降低。西司他丁可预防细胞凋亡事件，并减少万古霉素诱导的抗增殖作用和严重的形态学变化。西司他丁还改善了暴露于万古霉素的RPTEC的长期恢复和存活，并部分减弱了RPTEC对万古霉素的摄取。另一方面，西司他丁对万古霉素诱导的坏死或抗生素的杀菌作用没有影响。这项研究表明，西司他丁保护万古霉素诱导的近端小管凋亡，并增加细胞活力，而不损害万古霉素的抗菌作用。有益作用至少部分归因于RPTEC中万古霉素蓄积减少。
Vancomycin is a very effective antibiotic for treatment of severe infections. However, its use in clinical practice is limited by nephrotoxicity. Cilastatin is a dehydropeptidase I inhibitor that acts on the brush border membrane of the proximal tubule to prevent accumulation of imipenem and toxicity. The aim of this study was to investigate the potential protective effect of cilastatin on vancomycin-induced apoptosis and toxicity in cultured renal proximal tubular epithelial cells (RPTECs). Porcine RPTECs were cultured in the presence of vancomycin with and without cilastatin. Vancomycin induced dose-dependent apoptosis in cultured RPTECs, with DNA fragmentation, cell detachment, and a significant decrease in mitochondrial activity. Cilastatin prevented apoptotic events and diminished the antiproliferative effect and severe morphological changes induced by vancomycin. Cilastatin also improved the long-term recovery and survival of RPTECs exposed to vancomycin and partially attenuated vancomycin uptake by RPTECs. On the other hand, cilastatin had no effects on vancomycin-induced necrosis or the bactericidal effect of the antibiotic. This study indicates that cilastatin protects against vancomycin-induced proximal tubule apoptosis and increases cell viability, without compromising the antimicrobial effect of vancomycin. The beneficial effect could be attributed, at least in part, to decreased accumulation of vancomycin in RPTECs.