Metabolic rewiring of the hypertensive kidney
Metabolic rewiring of the hypertensive kidney
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DOI：
10.1126/scisignal.aax9760
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发表时间：
2019-12-10
影响因子：
7.3
通讯作者：
Siuzdak, Gary
中科院分区：
文献类型：
--
作者：
Rinschen, Markus M.;Palygin, Oleg;Siuzdak, Gary
高血压是发达国家的一种持续流行病，与肾脏疾病密切相关。在这里，我们应用代谢组学，磷酸蛋白质组学和蛋白质组学策略来分析高血压损伤对肾脏的影响，我们的数据揭示了高血压诱导的肾小球硬化的代谢方面，包括疾病早期阶段的脂质分解和回补途径的激活，以再生能量当量来对抗压力。例如，胶原蛋白合成所需的支链氨基酸和脯氨酸在早期时间点在肾小球中耗尽。此外，代谢应激的指标反映了低量的ATP和NADH以及来自脂质分解的氧化脂质的丰度增加。这些过程是肾小球特有的，其中代谢信号通过mTOR和AMPK信号传导发生。定量磷酸化蛋白质组学结合计算模型表明，这些过程控制关键分子在肾小球，特别是足细胞，包括细胞骨架成分和GTP结合蛋白，这将是预期竞争减少量的GTP在早期的时间点。结果，肾小球显示中心碳代谢、氨基酸降解和脂质氧化的代谢酶表达增加，这是在先前发表的其他疾病模型和肾小球损伤患者的研究中观察到的结果。总体而言，多层组学提供了高血压肾损害的概述，并表明代谢或饮食干预可以预防和治疗肾小球疾病和高血压诱导的肾病。
Hypertension is a persistent epidemic across the developed world that is closely associated with kidney disease. Here, we applied a metabolomic, phosphoproteomic, and proteomic strategy to analyze the effect of hypertensive insults on kidneys.Our data revealed the metabolic aspects of hypertension-induced glomerular sclerosis, including lipid breakdown at early disease stages and activation of anaplerotic pathways to regenerate energy equivalents to counter stress. For example, branched-chain amino acids and proline, required for collagen synthesis, were depleted in glomeruli at early time points. Furthermore, indicators of metabolic stress were reflected by low amounts of ATP and NADH and an increased abundance of oxidized lipids derived from lipid breakdown. These processes were specific to kidney glomeruli where metabolic signaling occurred through mTOR and AMPK signaling. Quantitative phosphoproteomics combined with computational modeling suggested that these processes controlled key molecules in glomeruli and specifically podocytes, including cytoskeletal components and GTP-binding proteins, which would be expected to compete for decreasing amounts of GTP at early time points. As a result, glomeruli showed increased expression of metabolic enzymes of central carbon metabolism, amino acid degradation, and lipid oxidation, findings observed in previously published studies from other disease models and patients with glomerular damage. Overall, multilayered omics provides an overview of hypertensive kidney damage and suggests that metabolic or dietary interventions could prevent and treat glomerular disease and hypertension-induced nephropathy.