Abstract 052: Vascular Endothelin-1 Mediates Hyperoxia-induced Cellular Stress In Kidney Vessels

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2023-09, Vol.80 (Suppl_1)
• Main Authors: Biswal, Sara N, Johnston, William A, Kraus, Abigayle C, Coleman, Gabriel J, De Miguel, Carmen
• Format: Article
• Language: English
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hyp.80.suppl_1.052

Abstract only Despite its common use in the clinic, therapeutic oxygen supplementation can result in organdamage. We recently reported in a mouse model that hyperoxia leads to elevated levels ofendothelin-1 (ET-1) in plasma and kidney, as well as exaggerated extracellular matrixdeposition, cell death and expression of mitochondria-related genes in the kidney. ET-1 is avasoactive peptide that is linked to various forms of cell stress pathways and kidney damage;however, the specific role that vasculature-derived ET-1 may play in hyperoxia-induced cellularstress in this organ is unknown. We hypothesized that, during hyperoxia, the lack ofvasculature-derived ET-1 results in ameliorated activation of endoplasmic reticulum andmitochondrial stress in kidney vessels. Male and female floxed ET-1 and vascular endothelialcell ET-1 knockout (VEET KO) mice were exposed to >95% O2 for 72 hours. After this time,mice were sacrificed, and renal vessels were isolated. Expression of genes involved inendoplasmic reticulum (ER) and mitochondrial stress was assessed by RT-PCR. Absence ofET-1 in the vasculature led to a significantly decreased expression of the ER stress marker ATF-4 after hyperoxia (floxed ET-1 vs. VEET KO: 1 ± 0.1 vs. 0.58 ± 0.08, n=8-12/group,p=0.0036). In response to high oxygen, VEET KO mice also presented with reduced expressionof mitochondrial genes FIS1 (1 ± 0.14 vs. 0.67 ± 0.15, p=0.0036), MFN2 (1 ± 0.16 vs. 0.58 ±0.12, p=0.0495), and PINK1 (1 ± 0.18 vs. 0.73 ± 0.28, p=0.048). No sex differences weredetected. Our data demonstrate that vascular ET-1 stimulates ER stress and mitochondrialstress pathways in the kidney vessels during hyperoxia, possibly inducing downstream kidneydamage. Our findings may provide new insights into novel therapeutic targets to preventhyperoxia-induced organ damage.