Journal Article Epublish
PubMed: 40244015 DOI: 10.3390/ijms26073214
Hydroxyurea Mitigates Heme-Induced Inflammation and Kidney Injury in Humanized Sickle Cell Mice.
Int J Mol Sci 26(7)
Authors: William Kwaku Agbozo, Wesley Solomon, Cecilia Elorm Lekpor, Isaac Joe Erskine, Babayewa Oguljahan, Alaijah Bashi, Adriana Harbuzariu, Adel Driss, Samuel Adjei, Lily Paemka, Solomon Fifii Ofori-Acquah, Jonathan K Stiles
Affiliations
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA.
- Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, P.O. Box LG 25 Legon-Accra, Ghana.
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), College of Basic and Applied Sciences, University of Ghana, P.O. Box LG 25 Legon-Accra, Ghana.
- Department of Pathology, Korle-Bu Teaching Hospital, P.O. Box 77 Korle Bu-Accra, Ghana.
- Center for Laboratory Animal Resources, Morehouse School of Medicine, Atlanta, GA 30310, USA.
- Stem Cell and Organoids Core, Emory University, Atlanta, GA 30322, USA.
- Department of Animal Experimentation, Noguchi Memorial Institute for Medical Research, University of Ghana, P.O. Box LG 581 Legon-Accra, Ghana.
- West African Genetic Medicine Center (WAGMC), University of Ghana, P.O. Box LG 25 Legon-Accra, Ghana.
Abstract
Kidney disorders significantly contribute to morbidity and mortality in sickle cell disease (SCD). Acute kidney injury (AKI), a major risk factor for chronic kidney disease (CKD), often arises from intravascular hemolysis, where plasma cell-free heme drives AKI through inflammatory and oxidative stress mechanisms. Hydroxyurea (HU), a well-established SCD-modifying therapy, improves clinical outcomes, but its effects on systemic heme and inflammatory mediators of kidney injury remain underexplored. This study evaluated HU's impact on plasma heme, pro-inflammatory mediators, kidney injury, and renal histopathology in a sickle cell mouse model. Townes humanized sickle cell mice (HbSS) and non-sickle (HbAA) controls were treated with HU or vehicle for two weeks. HU significantly reduced total plasma heme, lactate dehydrogenase, and pro-inflammatory cytokines (CXCL10, VEGF-A, IFN-γ) in HbSS mice. HU reduced renal injury biomarkers (cystatin C, NGAL) and improved renal histopathology, evidenced by reduced vascular congestion, glomerulosclerosis, and tubular damage. Interestingly, HU did not alter the levels of kidney repair biomarkers (clusterin and EGF). These findings suggest that HU mitigates kidney injury by reducing the deleterious effects of circulating heme and inflammation, supporting its potential to slow or prevent progressive kidney injury in SCD.
MeSH
Cells, Vascular Endothelial Growth Factor A, Anemia, Sickle Cell, Kidney, Heme, Biomarkers, Hemolysis, Acute Kidney Injury, Plasma, Hydroxyurea