Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
Cell Death Differ. 2023 Sep;30(9):2167-2186. doi: 10.1038/s41418-023-01198-x. Epub 2023 Aug 2.
Ferroptosis is a predominant contributor to renal ischemia reperfusion injury (IRI) after kidney transplant, evoking delayed graft function and poorer long-term outcomes. The wide propagation of ferroptosis among cell populations in a wave-like manner, developing the "wave of ferroptosis" causes a larger area of tubular necrosis and accordingly aggravates renal allograft IRI. In this study, we decipher a whole new metabolic mechanism underlying ferroptosis and propose a novel spreading pathway of the "wave of ferroptosis" in the renal tissue microenvironment, in which renal IRI cell-secreted small extracellular vesicles (IRI-sEVs) delivering lncRNA WAC-AS1 reprogram glucose metabolism in adjacent renal tubular epithelial cell populations by inducing GFPT1 expression and increasing hexosamine biosynthesis pathway (HBP) flux, and consequently enhances O-GlcNAcylation. Additionally, BACH2 O-GlcNAcylation at threonine 389 in renal tubular epithelial cells prominently inhibits its degradation by ubiquitination and promotes importin α5-mediated nuclear translocation. We present the first evidence that intranuclear BACH2 suppresses SLC7A11 and GPX4 transcription by binding to their proximal promoters and decreases cellular anti-peroxidation capability, accordingly facilitating ferroptosis. Inhibition of sEV biogenesis and secretion by GW4869 and knockout of lncRNA WAC-AS1 in IRI-sEVs both unequivocally diminished the "wave of ferroptosis" propagation and protected against renal allograft IRI. The functional and mechanistic regulation of IRI-sEVs was further corroborated in an allograft kidney transplant model and an in situ renal IRI model. In summary, these findings suggest that inhibiting sEV-mediated lncRNA WAC-AS1 secretion and targeting HBP metabolism-induced BACH2 O-GlcNAcylation in renal tubular epithelial cells may serve as new strategies for protecting against graft IRI after kidney transplant.
铁死亡是肾移植后肾缺血再灌注损伤 (IRI) 的主要原因，可导致移植物延迟功能和较差的长期结局。铁死亡在细胞群体中以波浪式的方式广泛传播，形成“铁死亡波”，导致更大面积的肾小管坏死，从而加重肾移植 IRI。在这项研究中，我们揭示了铁死亡的一个全新代谢机制，并提出了肾组织微环境中铁死亡“波”的一种新的传播途径，即肾 IRI 细胞分泌的小细胞外囊泡 (IRI-sEV) 通过诱导 GFPT1 表达和增加己糖胺生物合成途径 (HBP) 通量，从而改变相邻肾小管上皮细胞群体的葡萄糖代谢，将 lncRNA WAC-AS1 传递到细胞内。由此增强 O-GlcNAcylation。此外，BACH2 在肾小管上皮细胞中的苏氨酸 389 上的 O-GlcNAcylation 显著抑制其通过泛素化降解，并促进导入蛋白 α5 介导的核转位。我们首次提供证据表明，核内 BACH2 通过结合其近端启动子抑制 SLC7A11 和 GPX4 的转录，并降低细胞的抗氧化能力，从而促进铁死亡。通过 GW4869 抑制 sEV 的生物发生和分泌以及在 IRI-sEV 中敲除 lncRNA WAC-AS1，都可以明确地减少“铁死亡波”的传播并防止肾移植 IRI。在同种异体肾移植模型和原位肾 IRI 模型中进一步证实了 IRI-sEV 的功能和机制调节。总之，这些发现表明，抑制 sEV 介导的 lncRNA WAC-AS1 分泌和靶向肾小管上皮细胞中 HBP 代谢诱导的 BACH2 O-GlcNAcylation 可能成为防止肾移植后移植物 IRI 的新策略。
