Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy.
Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy.
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DOI：
10.1038/nm.3092
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发表时间：
2013-04
期刊：
影响因子：
82.9
通讯作者：
Boletta A
中科院分区：
文献类型：
--
作者：
Rowe I;Chiaravalli M;Mannella V;Ulisse V;Quilici G;Pema M;Song XW;Xu H;Mari S;Qian F;Pei Y;Musco G;Boletta A
常染色体显性遗传性多囊肾病（ADPKD）是一种常见的遗传性疾病，其特征是双侧肾囊肿形成。最近对ADPKD中失调的信号级联的鉴定导致了几项临床试验的启动，但仍然缺乏批准的治疗方法。在这里，我们使用代谢组学方法确定ADPKD的致病途径，可以安全地靶向治疗。我们发现PKD 1突变导致细胞、PKD小鼠模型和人源ADPKD肾脏中糖酵解增强。葡萄糖剥夺减少增殖和敏感PKD 1突变细胞凋亡。值得注意的是，用2-脱氧葡萄糖（2DG）治疗两种不同的PKD小鼠模型改善了肾体积、囊性指数和降低的增殖率。这些代谢改变依赖于ERK途径，其通过一方面抑制LKB 1-AMPK轴同时另一方面激活mTORC 1-糖酵解级联以双重方式起作用。增强的代谢率进一步抑制AMPK。AMPK的强制激活在恢复正常ERK活性的负反馈回路中起作用。总之，这些数据表明，缺陷的葡萄糖代谢密切参与ADPKD的病理生物学。我们的研究结果提供了一个强有力的理由，一个新的治疗模式，使用现有的药物，无论是单独或组合。
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation. Recent identification of signaling cascades de-regulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking. Using a metabolomic approach here we identify a pathogenic pathway in ADPKD which can be safely targeted for therapy. We show that mutation in PKD1 results in enhanced glycolysis in cells, in a murine model of PKD, and in human-derived ADPKD kidneys. Glucose deprivation reduced proliferation and sensitized PKD1 mutant cells to apoptosis. Notably, treatment of two distinct PKD mouse models with 2-deoxyglucose (2DG) ameliorates kidney volume, cystic index and reduced proliferation rates. These metabolic alterations depend on the ERK pathway acting in a dual manner by inhibiting the LKB1-AMPK axis on the one hand while activating the mTORC1-glycolytic cascade on the other. Enhanced metabolic rates further inhibit AMPK. Forced activation of AMPK acts in a negative feedback loop restoring normal ERK activity. Taken together, these data indicate that defective glucose metabolism is intimately involved in the pathobiology of ADPKD. Our findings provide a strong rationale for a novel therapeutic paradigm using existing drugs, either individually or in combination.