Tuberous sclerosis 1 (Tsc1) mediated mTORC1 activation promotes glycolysis in tubular epithelial cells in kidney fibrosis
Tuberous sclerosis 1 (Tsc1) mediated mTORC1 activation promotes glycolysis in tubular epithelial cells in kidney fibrosis
复制标题
结节性硬化症 1 (Tsc1) 介导的 mTORC1 激活促进肾纤维化肾小管上皮细胞的糖酵解
DOI：
10.1016/j.kint.2020.03.035
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发表时间：
2020-09-01
影响因子：
19.6
通讯作者：
Jiang, Lei
中科院分区：
文献类型：
--
作者：
Cao, Hongdi;Luo, Jing;Jiang, Lei
能量重新编程为糖酵解与慢性肾脏疾病的发生密切相关。结节硬化症复合体1(TSC1)是哺乳动物靶标雷帕霉素复合体1(MTORC1)信号的重要负调控因子，也是糖酵解的关键调节点。在这里，我们研究了TSC1是否可以通过调节近端肾小管上皮细胞的糖酵解来介导肾间质纤维化的进展。我们通过单侧输尿管结扎诱导了纤维化肾小管上皮细胞mTORC1信号的激活。这导致肾小管上皮细胞增殖增加，糖酵解酶表达上调。预先与雷帕霉素孵育可抑制mTORC1的激活，并取消促进的糖酵解和肾小管上皮细胞的增殖。此外，抑制TSC1的表达促进了大鼠肾上皮细胞系NRK-52E的糖酵解。小鼠近端肾小管中TSC1的特异性缺失导致肾脏增大，其特征是肾小管上皮细胞高比例增殖，肾小管扩张并伴有囊性形成，并伴有大量间质纤维化和糖酵解升高。糖酵解抑制剂2-脱氧葡萄糖显著改善小鼠肾小管上皮细胞的增殖、囊变和肾纤维化。因此，我们的发现表明，TSC1相关的mTORC1信号通过调节近端肾小管上皮细胞的糖酵解来介导肾间质纤维化的进展。
Energy reprogramming to glycolysis is closely associated with the development of chronic kidney disease. As an important negative regulatory factor of the mammalian target of rapamycin complex 1 (mTORC1) signal, tuberous sclerosis complex 1 (Tsc1) is also a key regulatory point of glycolysis. Here, we investigated whether Tsc1 could mediate the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells. We induced mTORC1 signal activation in tubular epithelial cells in kidneys with fibrosis via unilateral ureteral occlusion. This resulted in increased tubular epithelial cell proliferation and glycolytic enzyme upregulation. Prior incubation with rapamycin inhibited mTORC1 activation and abolished the enhanced glycolysis and tubular epithelial cell proliferation. Furthermore, knockdown of Tsc1 expression promoted glycolysis in the rat kidney epithelial cell line NRK-52E. Specific deletion of Tsc1 in the proximal tubules of mice resulted in enlarged kidneys characterized by a high proportion of proliferative tubular epithelial cells, dilated tubules with cyst formation, and a large area of interstitial fibrosis in conjunction with elevated glycolysis. Treatment of the mice with the glycolysis inhibitor 2-deoxyglucose notably ameliorated tubular epithelial cell proliferation, cystogenesis, and kidney fibrosis. Thus, our findings suggest that Tsc1-associated mTORC1 signaling mediates the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells.