Luan Yingyi, Huang Enping, Huang Jiajia, Yang Zhenjia, Zhou Zhipeng, Liu Yan, Wang Conglin, Wu Ming
Department of Infection and Critical Care Medicine, Shenzhen Second People's Hospital & First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen 518035, China.
Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University; Beijing Maternal and Child Health Care Hospital Beijing 100026, China.
J Transl Int Med. 2023 Jul 5;11(2):178-188. doi: 10.2478/jtim-2023-0092. eCollection 2023 Jul.
Myoglobin released by rhabdomyolysis (RM) is considered to be involved in pathogenesis of kidney disease caused by crush injury, but whether high level of serum myoglobin predisposes patients to acute kidney injury (AKI) and its molecular mechanisms are still unclear in exertional heatstroke (EHS). We aimed to determine the association and potential mechanism of myoglobin and AKI, and further investigate the targeted therapeutic agents for myoglobinemia.
Serum myoglobin concentrations in patients with EHS were measured at admission, 24 h and 48 h after admission and discharge. The risk of AKI at 48 h was the primary outcome; the secondary outcome was composite outcome events with myoglobin levels and AKI at discharge and death at 90 days. In experimental studies, we further investigated the mechanisms of human kidney proximal tubular (HK-2) cells that were exposed to human myoglobin under heat stress conditions and the effect of baicalein.
Our measurements showed that the highest myoglobin quartile (. the lowest) had an adjusted odds ratio (OR) of 18.95 (95% confidence interval [CI], 6.00-59.83) for AKI and that the OR (. quartile 2) was 7.92 (95% CI, 1.62-38.89) for the secondary outcome. The survival rate of HK-2 cells treated with myoglobin under heat stress was significantly decreased, and the production of Fe2+ and reactive oxygen species (ROS) was markedly increased, accompanied by changes in ferroptosis proteins, including increased p53, decreased SLC7A11 and GPX4, and alterations in endoplasmic reticulum stress (ERS) marker proteins. Treatment with baicalein attenuated HK-2 cell ferroptosis induced by myoglobin under heat stress through inhibition of ERS.
High myoglobin was associated with AKI in the EHS, and its mechanisms involved ERS-associated ferroptosis. Baicalein may be a potential therapeutic drug for the treatment of AKI in patients with high myoglobin induced by rhabdomyolysis following EHS.
横纹肌溶解症（RM）释放的肌红蛋白被认为与挤压伤所致肾病的发病机制有关，但在劳力性热射病（EHS）中，血清肌红蛋白水平升高是否会使患者易患急性肾损伤（AKI）及其分子机制仍不清楚。我们旨在确定肌红蛋白与AKI的关联及潜在机制，并进一步研究针对肌红蛋白血症的靶向治疗药物。
在入院时、入院后24小时和48小时以及出院时测量EHS患者的血清肌红蛋白浓度。48小时时发生AKI的风险为主要结局；次要结局为出院时肌红蛋白水平和AKI以及90天时死亡的复合结局事件。在实验研究中，我们进一步研究了热应激条件下暴露于人类肌红蛋白的人肾近端小管（HK-2）细胞的机制以及黄芩苷的作用。
我们的测量结果显示，最高肌红蛋白四分位数（相对于最低四分位数）发生AKI的校正比值比（OR）为18.95（95%置信区间[CI]，6.00-59.83），次要结局的OR（相对于第二四分位数）为7.92（95%CI，1.62-38.89）。热应激下用肌红蛋白处理的HK-2细胞存活率显著降低，Fe2+和活性氧（ROS）的产生明显增加，同时铁死亡蛋白发生变化，包括p53增加、SLC7A11和GPX4减少，以及内质网应激（ERS）标记蛋白改变。黄芩苷治疗通过抑制ERS减轻了热应激下肌红蛋白诱导的HK-2细胞铁死亡。
高肌红蛋白与EHS中的AKI相关，其机制涉及ERS相关的铁死亡。黄芩苷可能是治疗EHS后横纹肌溶解所致高肌红蛋白患者AKI的潜在治疗药物。
