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.

中文翻译：

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高血压肾的代谢重新布线。

高血压在发达国家是一种持续流行的疾病，与肾脏疾病密切相关。在这里，我们应用代谢组学、磷酸化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引起的肾小球硬化的代谢方面，包括疾病早期的脂质分解和恢复性途径的激活以再生能量当量以应对压力。例如，胶原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被耗尽。此外，代谢压力的指标反映在少量的 ATP 和 NADH 以及来自脂质分解的氧化脂质丰度增加。这些过程是肾小球特有的，其中代谢信号通过 mTOR 和 AMPK 信号发生。定量磷酸蛋白质组学与计算模型相结合表明，这些过程控制了肾小球中的关键分子，特别是足细胞，包括细胞骨架成分和 GTP 结合蛋白，预计它们将在早期竞争减少量的 GTP。结果，肾小球显示出中枢碳代谢、氨基酸降解和脂质氧化的代谢酶表达增加，这些发现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。全面的，