Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian, China.
Elife. 2023 Feb 1;12:e80647. doi: 10.7554/eLife.80647.
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 -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 -knockout mice exhibited significantly increased medullary ferroptosis following water restriction. Collectively, these findings reveal that 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.
肾髓质的高渗性对于尿液浓缩和水稳态至关重要。然而，肾髓质集合管（MCD）细胞在恶劣的高渗应激下如何存活和发挥功能仍不清楚。通过 RNA-Seq，我们鉴定出 SLC38A2 是 MCD 细胞中一种新的渗透压响应性中性氨基酸转运体。MCD 细胞中的高渗诱导细胞死亡主要通过铁死亡发生，而过表达 SLC38A2 可显著减轻这种细胞死亡，而 -基因缺失或沉默则会加重这种细胞死亡。机制研究表明，SLC38A2 的渗透压保护作用依赖于 mTORC1 的激活。此外，一项体内研究表明，水限制后 -敲除小鼠的髓质铁死亡明显增加。总之，这些发现表明 是肾髓质中重要的渗透压响应基因，并为 SLC38A2 通过 mTORC1 信号通路在保护 MCD 细胞免受高渗诱导的铁死亡中发挥的关键作用提供了新的见解。
