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Hydroxyurea Mitigates Heme-Induced Inflammation and Kidney Injury in Humanized Sickle Cell Mice
William Kwaku Agbozo1,2,3, Wesley Solomon1, Cecilia Elorm Lekpor1
1Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA.
International Journal of Molecular Sciences
|April 17, 2025
Summary
Hydroxyurea (HU) reduces kidney injury in sickle cell disease (SCD) by lowering harmful heme levels and inflammation. This therapy shows potential in preventing progressive kidney damage in SCD patients.
Area of Science:
- Nephrology
- Hematology
- Pharmacology
Background:
- Kidney disorders are a major cause of illness and death in sickle cell disease (SCD).
- Acute kidney injury (AKI), a precursor to chronic kidney disease (CKD), is often caused by intravascular hemolysis and cell-free heme, leading to inflammation and oxidative stress.
- Hydroxyurea (HU) is a standard SCD treatment, but its specific effects on heme mediators and kidney injury are not fully understood.
Purpose of the Study:
- To investigate the impact of hydroxyurea (HU) on plasma heme, inflammatory markers, kidney injury, and renal pathology in a sickle cell disease mouse model.
- To assess HU's influence on systemic heme levels and pro-inflammatory cytokines in sickle cell mice.
Main Methods:
- Townes humanized sickle cell mice (HbSS) and non-sickle (HbAA) controls were administered HU or a vehicle for two weeks.
- Plasma heme, lactate dehydrogenase, pro-inflammatory cytokines (CXCL10, VEGF-A, IFN-γ), and kidney injury biomarkers (cystatin C, NGAL) were measured.
- Renal histopathology was analyzed for signs of vascular congestion, glomerulosclerosis, and tubular damage.
Main Results:
- HU significantly decreased plasma heme, lactate dehydrogenase, and pro-inflammatory cytokines in HbSS mice.
- Treatment with HU led to reduced levels of kidney injury biomarkers (cystatin C, NGAL) in sickle cell mice.
- Renal histopathology showed improvements, including reduced vascular congestion, glomerulosclerosis, and tubular damage, in HU-treated HbSS mice compared to controls.
- HU did not affect kidney repair biomarkers such as clusterin and EGF.
Conclusions:
- Hydroxyurea mitigates kidney injury in sickle cell disease by reducing circulating heme and systemic inflammation.
- These findings support the potential of HU in slowing or preventing the progression of kidney disease in individuals with SCD.
- HU's mechanism involves dampening the inflammatory and oxidative stress pathways driven by cell-free heme.
