Serum myoglobin modulates kidney injury via inducing ferroptosis after exertional heatstroke

Yingyi Luan; Enping Huang; Jiajia Huang; Zhenjia Yang; Zhipeng Zhou; Yan Liu; Conglin Wang; Ming Wu

doi:10.2478/jtim-2023-0092

Serum myoglobin modulates kidney injury via inducing ferroptosis after exertional heatstroke

J Transl Int Med. 2023 Jul 5;11(2):178-188. doi: 10.2478/jtim-2023-0092. eCollection 2023 Jul.

Authors

Yingyi Luan^{1

2}, Enping Huang³, Jiajia Huang^{1

4}, Zhenjia Yang^{1

4}, Zhipeng Zhou¹, Yan Liu¹, Conglin Wang⁵, Ming Wu^{1

4}

Affiliations

¹ Department of Infection and Critical Care Medicine, Shenzhen Second People's Hospital & First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen 518035, China.
² Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University; Beijing Maternal and Child Health Care Hospital Beijing 100026, China.
³ Department of Forensic Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China.
⁴ Shantou University Medical College, Shantou 515041, Guangdong Province, China.
⁵ Department of critical care medicine, General Hospital of Southern Theatre Command of PLA, Guangzhou 510010, Guangdong Province, China.

Abstract

Background and objectives: 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.

Methods: 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.

Results: Our measurements showed that the highest myoglobin quartile (vs. 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 (vs. 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.

Conclusions: 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.

Keywords: acute kidney injury; baicalein; endoplasmic; exertional heatstroke; ferroptosis; myoglobin; reticulum stress.

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81873943), Sanming Project of Medicine in Shenzhen (SZSM20162011), Shenzhen Science and Technology Innovation Commission (JCYJ20190806163603504), and Shenzhen Second People’s Hospital Clinical Research Fund of Guangdong Province High-Level Hospital Construction Project (Grant No. 20173357201815, No20193357003, No. 20203357014).