Iron-associated lipid peroxidation contributes to rhabdomyolysis-induced acute kidney injury in sickle cell mice

This is the authors' abstract. We don't add key points for this paper.

Individuals with sickle cell disease (SCD) are susceptible to acute kidney injury (AKI), and rhabdomyolysis may impose an additional renal burden through the release of iron-containing heme proteins and amplification of oxidative stress. We previously showed that glycerol-induced rhabdomyolysis causes disproportionate renal iron accumulation and AKI in homozygous humanized sickle cell (SS) mice. Here, we investigated whether iron-associated lipid peroxidation contributes to this injury. Bulk RNA sequencing of SS kidneys after rhabdomyolysis revealed enrichment of pathways related to reactive oxygen species, redox homeostasis, glutathione metabolism, oxidoreductase activity, and lipid metabolism. Rhabdomyolysis increased circulating hemoglobin, heme, and lactate dehydrogenase, consistent with increased hemolysis-related injury, and was accompanied by greater renal iron accumulation. Renal malondialdehyde levels and prostaglandin endoperoxide synthase 2 expression increased, whereas glutathione peroxidase 4 activity and glutathione peroxidase 1 immunoreactivity decreased, consistent with enhanced lipid peroxidation-associated stress and impaired antioxidant defense. Cardiac output and stroke volume declined modestly, but conventional indices of global systolic and diastolic function were largely preserved. Prophylactic treatment with ferrostatin-1, deferiprone, or hydroxyurea reduced renal iron accumulation and lipid peroxidation-associated changes. Each intervention also attenuated rhabdomyolysis-induced loss of glomerular filtration rate, elevations in AKI biomarkers, and histological tubular injury. Collectively, these findings support iron-associated lipid peroxidation as an important contributor to rhabdomyolysis-induced AKI in SCD and suggest that limiting iron-dependent oxidative injury may help preserve renal function in this high-risk setting.