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Sickle cell disease (SCD) is characterized by chronic hemolysis, inflammation, and progressive kidney injury which leads to renal failure and increased mortality rates with limited therapeutic options available. Neuregulin-1 (NRG-1) is a cytoprotective growth factor with anti-inflammatory and antioxidant properties and an established clinical safety profile in humans. Using Townes humanized sickle cell (HbSS) mice, we investigated whether NRG-1 mitigates kidney injury by reducing hemolytic and inflammatory mediators and enhancing renal cytoprotective and repair factors. NRG-1 treatment reduced plasma heme, lactate dehydrogenase, and pro-inflammatory cytokines levels, while increasing the proportion of circulating fetal hemoglobin-containing red blood cells (F-cells). Treatment mitigated urinary cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) elevations and improved renal histopathology, including reduced iron deposition, glomerular congestion, and sclerosis. NRG-1 also enhanced heme oxygenase-1 (HO-1) expression in HbSS kidneys and increased urinary renal repair biomarkers clusterin and epidermal growth factor (EGF). Collectively, these findings provide new mechanistic insight supporting further exploration of NRG-1 as a therapeutic agent for mitigating kidney injury in SCD.
Agbozo et al. (2026) studied this question.