Date of Award
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Program
Biomedical Sciences
Track
Cell Biology and Physiology
Research Advisor
Adebowale Adebiyi
Committee
Helena Parfenova; Junaith Mohamed; Kaushik Parthasarathi; Kenneth Ataga; Valeria Vasquez
Keywords
Acute Kidney Injury, Iron, Lipid Peroxidation, Oxidative Stress, Rhabdomyolysis, Sickle Cell Disease
Abstract
Sickle cell syndromes increase the risk of rhabdomyolysis, a potentially life-threatening condition stemming from the destruction of skeletal muscle fibers. Acute kidney injury (AKI), a major complication of rhabdomyolysis, contributes to long-term morbidity through the development of chronic kidney disease and cardiovascular disease. Both of these are leading causes of mortality in individuals with sickle cell syndromes, namely sickle cell disease (SCD). Despite the elevated risk of rhabdomyolysis-induced sudden death in this population, the underlying mechanisms that contribute to the increased severity of rhabdomyolysis-induced AKI in SCD remain poorly understood. A better understanding of these mechanisms is critical for highlighting potential therapeutics to reduce renal complications arising from rhabdomyolysis-induced AKI and improving outcomes for individuals with SCD. In this project, we demonstrate that transgenic SCD mice (Townes model) are susceptible to glycerol-induced rhabdomyolysis, with a 100% mortality rate within 8-24 hours following intramuscular glycerol injection. Five hours after glycerol injection, both non-sickling (AA) and sickling (SS) mice exhibited positive indicators of rhabdomyolysis, noted by significant increases in myoglobinuria and plasma creatine kinase levels, with SS mice showing more significant increases. In vivo cardiac imaging showed that glycerol-induced rhabdomyolysis caused mild yet expected cardiac effects that were not anticipated to confound the severity of rhabdomyolysis-induced AKI. Rhabdomyolysis was shown to aggravate hemolysis parameters in SS, but not AA, mice when total hemoglobin, plasma hemoglobin, plasma heme, and lactate dehydrogenase were evaluated. Spleen weights were found to be unchanged following rhabdomyolysis in both AA and SS mice. In contrast to AA mice, which showed virtually no evidence of kidney tissue iron accumulation, oxidative stress, or increased AKI biomarkers, SS mice displayed highly significant changes in all parameters, indicating that SS mice are highly sensitive to iron-induced oxidative stress and AKI. Investigating this further showed that SS mice had significant levels of iron-induced lipid peroxidation, as indicated by a reduction in GPX4 and an increase in 4-HNE. The use of antioxidants (TEMPOL, ferrostatin-1, and hydroxyurea) and iron chelators (deferiprone and, potentially, hydroxyurea) were able to ameliorate renal iron accumulation, oxidative stress, lipid peroxidation, and rhabdomyolysis-induced AKI in SS mice. These findings provide evidence that free iron, released from hemoglobin during hemolysis and myoglobin during rhabdomyolysis, contributes to the amplified severity of rhabdomyolysis-induced AKI in SCD mice. This free iron accumulates in the kidneys and gives rise to renal oxidative stress, lipid peroxidation, and AKI. As such, antioxidants and iron chelation provide potential therapeutic targets to mitigate the more severe outcomes of rhabdomyolysis-induced AKI in SCD.
ORCID
0000-0002-1991-4844
DOI
10.21007/etd.cghs.2025.0702
Recommended Citation
Williams, Jada De'Ann (0000-0002-1991-4844), "Rhabdomyolysis-induced Acute Kidney Injury in Sickle Cell Disease" (2025). Theses and Dissertations (ETD). Paper 722. http://dx.doi.org/10.21007/etd.cghs.2025.0702.
https://dc.uthsc.edu/dissertations/722