Abstract：
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.
摘要：
肾髓质的高渗透压对于尿液浓度和水稳态至关重要。然而,肾髓质集合管(MCD)细胞在严酷的高渗应激下如何存活和发挥功能尚不清楚.使用RNA-Seq，我们确定SLC38A2是MCD细胞中一种新型的渗透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性凋亡发生,SLC38A2过表达显着减弱，但Slc38a2基因缺失或沉默恶化。机制研究表明，SLC38A2的渗透保护作用取决于mTORC1的激活。此外，一项体内研究表明，Slc38a2敲除小鼠在限水后表现出髓质铁细胞凋亡显着增加。总的来说，这些发现揭示了Slc38a2是肾髓质中一个重要的渗透响应基因,并为SLC38A2通过mTORC1信号通路保护MCD细胞免受高渗透压诱导的铁细胞凋亡的关键作用提供了新的见解。
