The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury
The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury
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DOI：
10.1016/j.kint.2018.08.037
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发表时间：
2019-02-01
影响因子：
19.6
通讯作者：
Rinschen, Markus M.
中科院分区：
文献类型：
--
作者：
Spaeth, Martin R.;Bartram, Malte P.;Rinschen, Markus M.
急性肾损伤（AKI）导致显着的发病率和死亡率；不幸的是，缺乏预防或治疗 AKI 的策略。近年来，多种预处理方案已被证明可有效诱导啮齿动物模型的器官保护。在这里，我们在顺铂诱导的 AKI 小鼠模型中对其中两种干预措施（热量限制和低氧预处理）进行了表征，并通过在同一动物中获取多层组学数据（转录组、蛋白质组、N-降解组）和功能参数来研究其潜在机制。两种预处理方案均显着改善了顺铂引起的肾功能丧失，并且热量限制也诱导了脂质合成。生物信息分析揭示了影响细胞外空间、线粒体和转运蛋白的不依赖于 mRNA 的蛋白质组改变。有趣的是，我们的分析揭示了顺铂治疗后蛋白质和 RNA 表达的强烈分离，这与损伤程度密切相关。 N-降解组学分析表明，大多数转录后变化是由精氨酸特异性蛋白水解加工决定的。这包括通过预处理阻止的特征性顺铂激活补体特征。皮质实质内的淀粉样蛋白和急性期蛋白表现出类似的反应。对疾病相关分子模式的广泛分析表明，淀粉样蛋白 P 成分血清蛋白的转录独立沉积可能是微环境导致肾脏损伤的关键组成部分。这项原理验证研究通过关联表型和多层组学数据，为顺铂诱导的 AKI 发病机制以及器官保护的分子机制提供了新的见解。
Acute kidney injury (AKI) leads to significant morbidity and mortality; unfortunately, strategies to prevent or treat AKI are lacking. In recent years, several preconditioning protocols have been shown to be effective in inducing organ protection in rodent models. Here, we characterized two of these interventions-caloric restriction and hypoxic preconditioning-in a mouse model of cisplatin-induced AKI and investigated the underlying mechanisms by acquisition of multi-layered omic data (transcriptome, proteome, N-degradome) and functional parameters in the same animals. Both preconditioning protocols markedly ameliorated cisplatin-induced loss of kidney function, and caloric restriction also induced lipid synthesis. Bioinformatic analysis revealed mRNA-independent proteome alterations affecting the extracellular space, mitochondria, and transporters. Interestingly, our analyses revealed a strong dissociation of protein and RNA expression after cisplatin treatment that showed a strong correlation with the degree of damage. N-degradomic analysis revealed that most posttranscriptional changes were determined by arginine-specific proteolytic processing. This included a characteristic cisplatin-activated complement signature that was prevented by preconditioning. Amyloid and acute-phase proteins within the cortical parenchyma showed a similar response. Extensive analysis of disease-associated molecular patterns suggested that transcription-independent deposition of amyloid P-component serum protein may be a key component in the microenvironmental contribution to kidney damage. This proof-of-principle study provides new insights into the pathogenesis of cisplatin-induced AKI and the molecular mechanisms underlying organ protection by correlating phenotypic and multi-layered omics data.