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 (Kf). The increases in Kf may be due to enlarged filtration surface area and/or increased glomerular permeability (Palb). Previous studies have demonstrated that endothelin-1 (ET-1) contributes to Palb 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 Palb that may contribute to hyperfiltration in humanized sickle cell (HbSS) and control (HbAA) mice 8 to 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 Kf.  During the onset of hyperfiltration, plasma and glomerular ET-1 expression were associated with a greater increase in glomerular size and Kf in HbSS mice, regardless of sex. The pattern of Palb 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 Palb was significantly greater in males and delayed in time in females. Additionally, selective endothelin A (ETA) receptor antagonist prevented hyperfiltration in HbSS, regardless of sex. These resu...

Source: Clinical Science - July 3, 2019 Category: Biomedical Science Authors: Kasztan, M., Pollock, D. M. Tags: PublishAheadOfPrint Source Type: research