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Abstract：
Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1α and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1/HK2, ALDOA, ENO2, PKM, LDHA/LDHB, MCT4, PDHA1, PDK1/3, MPC1/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1α, a transcriptional coactivator for transcription factors PPARα, ERRα, and ERRγ, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention.
摘要：
在常染色体显性遗传多囊肾病（ADPKD）的实验研究中已经记录了细胞代谢的多种改变，并被认为是其发病机理的原因。阐明ADPKD中与肾囊肿代谢变化相关的分子通路和转录调节因子,我们比较了人类PKD1肾囊肿的整体基因表达数据，来自同一患者的微囊组织（MCT），和健康的人肾皮质组织样本.我们发现PKD1肾囊肿的基因表达谱与Warburg效应一致，基因途径的变化有利于细胞葡萄糖摄取和乳酸产生的增加。而不是丙酮酸氧化。此外,线粒体能量代谢在全球范围内受到抑制，与脂肪酸氧化相关的基因通路下调(FAO)，支链氨基酸（BCAA）降解，克雷布斯周期，和肾囊肿中的氧化磷酸化（OXPHOS）。激活mTORC1及其两个靶原癌基因，HIF-1α和MYC,被预测为驱动参与观察到的代谢重编程的多个基因的表达(例如，GLUT3,HK1/HK2,ALDOA,ENO2,PKM,LDHA/LDHB,MCT4，PDHA1，PDK1/3，MPC1/2，CPT2，BCAT1，NAMPT）；实际上，我们的数据证实了他们预测的表达模式.相反，我们发现AMPK抑制在肾囊肿中被预测。AMPK抑制与PGC-1α表达降低有关,转录因子PPARα的转录共激活因子，ERRα,和ERRγ，所有这些在调节氧化代谢和线粒体生物合成中起着关键作用。这些数据提供了ADPKD中代谢途径重编程的全面图谱，并突出了可以作为治疗干预目标的调控节点。
