Neutral amino acid transporter SLC38A2 protects renal medulla from hyperosmolarity-induced ferroptosis.
Neutral amino acid transporter SLC38A2 protects renal medulla from hyperosmolarity-induced ferroptosis.
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DOI：
10.7554/elife.80647
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发表时间：
2023-02-01
期刊：
影响因子：
7.7
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Du C;Xu H;Cao C;Cao J;Zhang Y;Zhang C;Qiao R;Ming W;Li Y;Ren H;Cui X;Luan Z;Guan Y;Zhang X
肾髓质的高渗性对于尿浓缩和水的稳态是必不可少的。然而，肾髓质集合管（MCD）细胞如何在苛刻的高渗应激下存活和发挥功能仍不清楚。使用RNA-Seq，我们鉴定了SLC 38 A2为MCD细胞中的新型的β-受体响应性中性氨基酸转运蛋白。高渗应激诱导的MCD细胞死亡主要通过铁凋亡发生，SLC 38 A2过表达可显著减弱铁凋亡，但Slc 38 a2基因缺失或沉默可加重铁凋亡。机制研究表明，SLC 38 A2的神经保护作用依赖于mTORC 1的激活。此外，一项体内研究表明，Slc 38 a2基因敲除小鼠在限水后表现出明显增加的髓铁下垂。总的来说，这些研究结果表明，SLC 38 A2是一个重要的肾脏髓质中的β-受体应答基因，并提供了新的见解SLC 38 A2在保护MCD细胞从高渗诱导的铁凋亡通过mTORC 1信号通路的关键作用。
Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and function under harsh hyperosmotic stress remains unclear. Using RNA-Seq, we identified SLC38A2 as a novel osmoresponsive neutral amino acid transporter in MCD cells. Hyperosmotic stress-induced cell death in MCD cells occurred mainly via ferroptosis, and it was significantly attenuated by SLC38A2 overexpression but worsened by Slc38a2-gene deletion or silencing. Mechanistic studies revealed that the osmoprotective effect of SLC38A2 is dependent on the activation of mTORC1. Moreover, an in vivo study demonstrated that Slc38a2-knockout mice exhibited significantly increased medullary ferroptosis following water restriction. Collectively, these findings reveal that Slc38a2 is an important osmoresponsive gene in the renal medulla and provide novel insights into the critical role of SLC38A2 in protecting MCD cells from hyperosmolarity-induced ferroptosis via the mTORC1 signalling pathway.