Neuregulin‐1 Mitigates Kidney Injury in Humanized Sickle Cell Mice

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.