Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury.
Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury.
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DOI：
10.1371/journal.pone.0184570
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Soleimani M
中科院分区：
文献类型：
--
作者：
Zahedi K;Barone S;Destefano-Shields C;Brooks M;Murray-Stewart T;Dunworth M;Li W;Doherty JR;Hall MA;Smith RD;Cleveland JL;Casero RA Jr;Soleimani M
顺铂引起的肾毒性限制了其在许多癌症患者中的使用。用顺铂治疗的小鼠肾脏中参与多胺分解代谢的酶、亚精胺/精胺 N1-乙酰转移酶 (SSAT) 和精胺氧化酶 (SMOX) 的表达增加。我们假设多胺分解代谢增强会导致顺铂急性肾损伤（AKI）中的组织损伤。使用基因敲除和化学抑制剂，研究了多胺分解代谢在顺铂 AKI 中的作用。缺乏 SSAT、SMOX 或中和多胺降解的有毒产物、H2O2 和氨基丙醛，可显着减轻顺铂 AKI 的严重程度。体外研究表明，细胞中 SSAT 的诱导和多胺分解代谢的增加会增加真核翻译起始因子 2α (eIF2α) 的磷酸化，并增强结合免疫球蛋白蛋白 BiP/GRP78) 和 CCAAT 增强子结合蛋白同源蛋白 (CHOP/GADD153) 的表达。这些内质网应激反应 (ERSR) 标记物的表达增加伴随着 caspase-3 的激活。这些结果表明，顺铂 AKI 中多胺降解的增强可能通过诱导 ERSR 和随后的细胞凋亡而导致肾小管损伤。为了支持上述观点，我们证明 SSAT 或 SMOX 基因的消除以及多胺分解代谢产物的中和调节 ERSR（例如降低 BiP 和 CHOP）和细胞凋亡（例如减少活化的 caspase-3）的发生。这些研究表明，增强的多胺分解代谢及其有毒产物是 ERSR 的重要介质，对顺铂 AKI 的发病机制至关重要。
Cisplatin-induced nephrotoxicity limits its use in many cancer patients. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX) increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI). Using gene knockout and chemical inhibitors, the role of polyamine catabolism in cisplatin AKI was examined. Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H2O2 and aminopropanal, significantly diminished the severity of cisplatin AKI. In vitro studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and enhances the expression of binding immunoglobulin protein BiP/GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153). The increased expression of these endoplasmic reticulum stress response (ERSR) markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP) and apoptosis (e.g. reduced activated caspase-3). These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI.
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影响因子：
5
作者：
Li, Shi-Yan;Gilbert, Sara A. B.;Li, Qun;Ren, Jun
通讯作者：
Ren, Jun
影响因子：
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作者：
Ozkok A;Edelstein CL
通讯作者：
Edelstein CL
影响因子：
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作者：
BRUNK, UT;ZHANG, H;OLLINGER, K
通讯作者：
OLLINGER, K
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作者：
Golab, Fereshteh;Kadkhodaee, Mehri;Soleimani, Manoocher
通讯作者：
Soleimani, Manoocher
影响因子：
4.8
作者：
Jell, Jason;Merali, Salim;Porter, Carl W.
通讯作者：
Porter, Carl W.