Lkb1 deficiency confers glutamine dependency in polycystic kidney disease.
Lkb1 deficiency confers glutamine dependency in polycystic kidney disease.
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DOI：
10.1038/s41467-018-03036-y
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发表时间：
2018-02-26
影响因子：
16.6
通讯作者：
Carroll TJ
中科院分区：
文献类型：
--
作者：
Flowers EM;Sudderth J;Zacharias L;Mernaugh G;Zent R;DeBerardinis RJ;Carroll TJ
多囊肾病是一种常见的遗传性疾病，其特征是肾脏中充满液体的囊肿生长。一些研究报道丝氨酸-苏氨酸激酶Lkb 1在PKD中失调。在这里，我们表明，在胚胎输尿管芽的LKB 1基因消融没有影响小管的形成，维护，或增长。然而，Lkb 1和Tsc 1（一种mTOR阻遏物）的共同消融导致PKD的早期发展、侵袭性形式。我们发现Lkb 1和Pkd 1的缺失都使细胞依赖于谷氨酰胺生长。代谢组学分析表明，Lkb 1突变的肾脏需要谷氨酰胺的非必需氨基酸和谷胱甘肽代谢。在Lkb 1/Tsc 1和Pkd 1突变小鼠中抑制谷氨酰胺代谢可显著降低囊肿进展。因此，我们确定了Lkb 1在肾上皮细胞内谷氨酰胺代谢中的作用，并建议靶向谷氨酰胺代谢的药物可能有助于减少PKD的囊肿数量和/或大小。多囊肾病（PKD）是一种常见的肾脏疾病。Flowers及其同事发现，在PKD中下调的Lkb 1的丢失使肾细胞依赖于谷氨酰胺生长，并表明谷氨酰胺代谢的抑制可能会阻止PKD中的囊肿发育。
Polycystic kidney disease (PKD) is a common genetic disorder characterized by the growth of fluid-filled cysts in the kidneys. Several studies reported that the serine-threonine kinase Lkb1 is dysregulated in PKD. Here we show that genetic ablation of Lkb1 in the embryonic ureteric bud has no effects on tubule formation, maintenance, or growth. However, co-ablation of Lkb1 and Tsc1, an mTOR repressor, results in an early developing, aggressive form of PKD. We find that both loss of Lkb1 and loss of Pkd1 render cells dependent on glutamine for growth. Metabolomics analysis suggests that Lkb1 mutant kidneys require glutamine for non-essential amino acid and glutathione metabolism. Inhibition of glutamine metabolism in both Lkb1/Tsc1 and Pkd1 mutant mice significantly reduces cyst progression. Thus, we identify a role for Lkb1 in glutamine metabolism within the kidney epithelia and suggest that drugs targeting glutamine metabolism may help reduce cyst number and/or size in PKD. Polycystic kidney disease (PKD) is characterized by the formation of large fluid-filled cysts. Here Flowers and colleagues show that loss of Lkb1, downregulated in PKD, renders kidney cells dependent on glutamine for growth, and suggest that inhibition of glutamine metabolism may prevent cyst development in PKD.
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影响因子：
11.8
作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.1312570111
发表时间：
2014-02-18
影响因子：
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DOI：
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发表时间：
2006-12-22
影响因子：
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作者：
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