Rhabdomyolysis aggravates renal iron accumulation and acute kidney injury in a humanized mouse model of sickle cell disease

Abstract

Individuals with sickle cell disease (SCD) are at greater risk of rhabdomyolysis, a potentially life-threatening condition 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. In the present study, we show that, unlike their control non-sickling (AA) counterparts, transgenic homozygous SCD (SS; Townes model) mice exhibited 100% mortality 8–24 h after intramuscular glycerol injection. Five hours after glycerol injection, SS mice showed a more significant increase in myoglobinuria and plasma creatine kinase levels than AA mice. Basal plasma heme and kidney tissue iron levels were significantly higher in SS than in AA mice. In contrast to AA, glycerol-induced rhabdomyolysis aggravated these parameters in SS mice. Rhabdomyolysis also amplified oxidative stress in SS compared to AA mice. Glycerol-treated SS mice exhibited worse renal function, exemplified by a reduction in GFR with a corresponding increase in plasma and urinary biomarkers of early AKI and renal tubular damage. The free radical scavenger and Fenton chemistry inhibitor, TEMPOL, ameliorated rhabdomyolysis-induced AKI in the SS mice. These findings demonstrate that oxidative stress driven by renal iron accumulation amplifies rhabdomyolysis-induced AKI in SCD mice.

Keywords:

• Rhabdomyolysis
• acute kidney injury
• iron
• oxidative stress
• sickle cell disease

Acknowledgments

The authors would like to acknowledge the UAB-UCSD O'Brien Core Center for Acute Kidney Injury Research for assistance with independent creatinine analysis.

Authors’ contributions

A.A. conceived and designed research. J.D.W., R.K., and J.M.A. performed experiments. F.P. performed histological analysis. A.A. and J.D.W. analyzed and interpreted results, prepared figures, and drafted the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The National Institutes of Health supported Dr. A. Adebiyi under the award numbers R01HL151735. J.D. Williams was supported by the National Heart, Lung, and Blood Institute Research Supplement under the award number R01HL151735-S. The content of this publication is solely the authors’ responsibility and does not necessarily represent the official views of the NIH.