Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Integrated Therapy for Chronic Kidney Disease, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Biochem Biophys Res Commun. 2023 Jul 23;666:137-145. doi: 10.1016/j.bbrc.2023.05.029. Epub 2023 May 9.
Acute kidney injury is an important global health concern as it is associated with high morbidity and mortality. Polyamines, essential for cell growth and proliferation, are known to inhibit cardiovascular disease. However, under conditions of cellular damage, toxic acrolein is produced from polyamines by the enzyme spermine oxidase (SMOX). We used a mouse renal ischemia-reperfusion model and human proximal tubule cells (HK-2) to investigate whether acrolein exacerbates acute kidney injury by renal tubular cell death. Acrolein visualized by acroleinRED was increased in ischemia-reperfusion kidneys, particularly in tubular cells. When HK-2 cells were cultured under 1% oxygen for 24 h, then switched to 21% oxygen for 24 h (hypoxia-reoxygenation), acrolein accumulated and SMOX mRNA and protein levels were increased. Acrolein induced cell death and fibrosis-related TGFB1 mRNA in HK-2 cells. Administration of the acrolein scavenger cysteamine suppressed the acrolein-induced upregulation of TGFB1 mRNA. Cysteamine also inhibited a decrease in the mitochondrial membrane potential observed by MitoTrackerCMXRos, and cell death induced by hypoxia-reoxygenation. The siRNA-mediated knockdown of SMOX also suppressed hypoxia-reoxygenation-induced acrolein accumulation and cell death. Our study suggests that acrolein exacerbates acute kidney injury by promoting tubular cell death during ischemia-reperfusion injury. Treatment to control the accumulation of acrolein might be an effective therapeutic option for renal ischemia-reperfusion injury.
急性肾损伤是一个重要的全球健康问题，因为它与高发病率和死亡率有关。多胺是细胞生长和增殖所必需的，已知可抑制心血管疾病。然而，在细胞损伤的情况下，多胺会被酶- 精脒氧化酶（SMOX）产生有毒的丙烯醛。我们使用了小鼠肾缺血再灌注模型和人近端肾小管细胞（HK-2）来研究丙烯醛是否通过肾小管细胞死亡加剧急性肾损伤。缺血再灌注肾脏中丙烯醛 RED 可视化的丙烯醛增加，特别是在肾小管细胞中。当 HK-2 细胞在 1%氧气中培养 24 小时，然后切换到 21%氧气 24 小时（缺氧复氧）时，丙烯醛积累，SMOX mRNA 和蛋白水平增加。丙烯醛诱导 HK-2 细胞死亡和纤维化相关 TGFB1 mRNA。丙烯醛清除剂半胱胺的给药抑制了丙烯醛诱导的 TGFB1 mRNA 的上调。半胱胺还抑制了 MitoTrackerCMXRos 观察到的线粒体膜电位下降，以及缺氧复氧诱导的细胞死亡。SMOX 的 siRNA 介导的敲低也抑制了缺氧复氧诱导的丙烯醛积累和细胞死亡。我们的研究表明，丙烯醛通过在缺血再灌注损伤期间促进肾小管细胞死亡来加剧急性肾损伤。控制丙烯醛积累的治疗可能是治疗肾缺血再灌注损伤的有效选择。
