LAUSR

Individuals with sickle cell disease (SCD) are at greater risk for developing rhabdomyolysis, a potentially life-threatening syndrome resulting from the breakdown of skeletal muscle fibers. Acute kidney injury (AKI) is one of the most severe complications of rhabdomyolysis. Chronic kidney and cardiovascular disease, which account for SCD mortality, are long-term consequences of AKI. Although SCD elevates the risks of rhabdomyolysis-induced sudden death, the mechanisms that underlie rhabdomyolysis-induced AKI in SCD are unclear. Here, we examined the effects of glycerol-induced rhabdomyolysis on kidney health in transgenic humanized mice that express human sickle hemoglobin (HbSS-Townes model). Unlike the control mice (AA), homozygous SCD mice (SS) exhibited 100% mortality 8-24 h after intramuscular glycerol injection. Five hours of glycerol-induced rhabdomyolysis caused a more significant increase in myoglobinuria and plasma creatine kinase levels in SS compared to AA mice. Since SS mice experience chronic hemolysis, releasing free heme and iron into the bloodstream, and the induction of rhabdomyolysis releases myoglobin, we examined heme and renal iron parameters in these mice. Basal plasma heme, iron accumulation, and kidney tissue ferric iron levels were significantly higher in SS than in AA control mice. In contrast to AA, rhabdomyolysis aggravated these parameters in SS mice. Rhabdomyolysis also amplified renal oxidative stress in SS compared to AA mice. SS mice exhibited worse renal function, exemplified by a significant decrease in GFR, increased plasma and urinary biomarkers of early AKI, and more significant renal tubular injury. The free radical scavenger TEMPOL ameliorated rhabdomyolysis-induced AKI in the SS mice. These findings suggest that rhabdomyolysis and subsequent AKI are heightened in SCD mice. It can also be inferred that oxidative stress driven by renal iron accumulation may underlie rhabdomyolysis-induced early AKI in SCD. NHLBI: R01 HL151735-01 and R01HL151735-S This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.