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; Dalian Key Laboratory for Nuclear Receptors in Major Metabolic Diseases, Dalian, China; Health Science Center, East China Normal University, Shanghai, China
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; Dalian Key Laboratory for Nuclear Receptors in Major Metabolic Diseases, Dalian, China
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.
