期刊
AUTOPHAGY
卷 16, 期 4, 页码 709-723出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2019.1635382
关键词
Autophagy; calcium oxalate; kidney stone; mechanistic target of rapamycin kinase; transcription factor EB
类别
资金
- Aichi Kidney Foundation
- Ministry of Education, Culture, Sports, Science and Technology, Japan [16K14595]
- Toukai Foundation for Technology
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [16K14595] Funding Source: KAKEN
Kidney stone disease is a lifestyle-related disease prevalent in developed countries; however, effective medical treatment for the disease is not yet well established. As cellular damage in renal tubular cells (RTCs) is responsible for the disease, here, we focused on the role of macroautophagy/autophagy in RTCs. We found that autophagic activity was significantly decreased in mouse RTCs exposed to calcium oxalate (CaOx) monohydrate crystals and in the kidneys of GFP-conjugated MAP1LC3B (microtubule- associated protein 1 light chain 3 beta) transgenic mice with CaOx nephrocalcinosis induced by glyoxylate. This caused accumulation of damaged intracellular organelles, such as mitochondria and lysosomes, the normal functioning of which is mediated by functional autophagy. An impairment of autophagy was also observed in the mucosa with plaques of CaOx kidney stone formers. We determined that the decrease in autophagy was caused by an upregulation of MTOR (mechanistic target of rapamycin kinase), which consequently resulted in the suppression of the upstream autophagy regulator TFEB (transcription factor EB). Furthermore, we showed that an MTOR inhibitor could recover a decrease in autophagy and alleviate crystal-cell interactions and the formation of crystals associated with increased inflammatory responses. Taken together, we conclude that autophagy compromised by MTOR deregulation is a fundamental feature in the pathology of kidney stone formation, and propose that chemical inhibition of MTOR could be a prospective strategy for disease suppression.
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