Serum myoglobin modulates kidney injury via inducing ferroptosis after exertional heatstroke

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.