Estrogen attenuates sepsis-induced renal vascular dysfunction in rats: Correlation with preservation of mitochondria-associated ER membranes.

AIMS: To determine whether estrogen (E2) protects against sepsis-induced renal vascular dysfunction and whether this effect is associated with preservation of mitochondria-associated endoplasmic reticulum membrane (MAM) in rats.

MATERIALS AND

METHODS

Male Wistar rats were randomly assigned to Sham, Sham+E2, Sepsis, and Sepsis+E2 groups. Sepsis was induced by intraperitoneal injection of allogeneic fecal filtrates (FF, 1 g/kg), and E2 (2 mg/kg) was administered intramuscularly 1 h after FF or vehicle injection. Renal vascular resistance (RI), peak systolic velocity (PSV), mean arterial pressure (MAP), and heart rate (HR) were measured. Serum creatinine (SCr), blood urea nitrogen (BUN), renal blood perfusion, isolated renal artery reactivity, MAM ultrastructure, and IP3R1 and VDAC1 expressions were assessed.

KEY FINDINGS: E2 treatment significantly improved 72 h survival, general condition, MAP, and HR in septic rats, attenuated sepsis-induced increases in SCr and BUN, reduced renal histopathological damage, and ameliorated renal blood perfusion. E2 decreased RI and PSV and restored norepinephrine-induced vasoconstriction and acetylcholine-induced endothelium-dependent vasodilation. Furthermore, E2 reversed sepsis-induced MAM abnormalities (decreased contact distance and increased ER-mitochondria contact coefficient) in both vascular smooth muscle and endothelial cells and normalized the sepsis-induced upregulation of IP3R1 and VDAC1 in both renal tissues and arteries.

SIGNIFICANCE: E2 attenuates sepsis-induced renal vascular dysfunction, which correlates with preservation of MAM ultrastructure and normalization of IP3R1 and VDAC1 expression in renal vascular cells. These findings identify MAM as a potential subcellular hub associated with estrogen-mediated vascular protection and provide a foundation for future mechanistic studies to define whether MAM directly contributes to these effects.