Impact of ET-1 and sex in glomerular hyperfiltration in humanized sickle cell mice

Hyperfiltration, highly prevalent early in sickle cell disease (SCD), is in part driven by an increase in ultrafiltration coefficient (K_f). The increase in K_f may be due to enlarged filtration surface area and/or increased glomerular permeability (P_alb). Previous studies have demonstrated that endothelin-1 (ET-1) contributes to P_alb changes in models of diabetes and SCD. Thus, we performed longitudinal studies of renal function to determine the relationship between ET-1 and glomerular size and P_alb that may contribute to hyperfiltration in humanized sickle cell (HbSS) and control (HbAA) mice at 8-32 weeks of age. HbSS mice were characterized by significant increases in plasma and glomerular ET-1 expression in both sexes although this increase was significantly greater in males. HbSS glomeruli of both males and females presented with a progressive and significant increase in glomerular size, volume, and K_f During the onset of hyperfiltration, plasma and glomerular ET-1 expression were associated with a greater increase in glomerular size and K_f in HbSS mice, regardless of sex. The pattern of P_alb augmentation during the hyperfiltration was also associated with an increase in glomerular ET-1 expression, in both male and female HbSS mice. However, the increase in P_alb was significantly greater in males and delayed in time in females. Additionally, selective endothelin A receptor (ET_A) antagonist prevented hyperfiltration in HbSS, regardless of sex. These results suggest that marked sex disparity in glomerular hyperfiltration may be driven, in part, by ET-1-dependent ultra-structural changes in filtration barrier components contributing to glomerular hyperfiltration in HbSS mice.