Increased Glomerular ET‐1 in Female Sickle Cell Mice is Abolished by Chronic Hydroxyurea Treatment

Abstract

Sickle cell disease (SCD) is associated with glomerular nephropathy leading to the chronic kidney disease. Endothelin (ET‐1), a powerful vasoconstrictor and pro‐inflammatory mediator, is increased in SCD patients and recent evidence suggests it can contribute to the development of glomerulopathy and decline in renal function in SCD. Currently, hydroxyurea is the only therapy demonstrating benefits for SCD patients due to its ability to increase fetal hemoglobin. Therefore, the aim of the study was to determine if elevated glomerular ET‐1 mRNA expression in sickle cell mice is reduced by hydroxyurea treatment and if sex differences exist in this response. Experiments utilized homozygous knockout‐transgenic sickle mice (humanized) from our in‐house colony. Hydroxyurea was administrated via drinking water and the concentration adjusted daily according to intake (50mg/kg/day) for 7 days. Glomeruli were isolated for ET‐1 mRNA. Female sickle cell mice had a 3‐fold increase in glomerular ET‐1 mRNA at baseline compared to male (3.07±0.21 vs. 1.07±0.16 fold change, p<0.05). After treatment with hydroxyurea female sickle cell mice had a significant reduction in ET‐1 expression (from 3.07±0.21 to 1.21±0.12 fold change, p<0.05). Hydroxyurea did not significantly alter glomerular ET‐1 production in male sickle cell. These data support the hypothesis that chronic treatment with hydroxyurea can reduce glomerular ET‐1 production, and possible renal pathologies associated with SCD. Further, sex differences in glomerular ET‐1 expression may play an important role in the development of sickle cell nephropathy.