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.