Abstract 5951: Role of Endothelin-1 in Upregulation of LOX-1 Expression in Hypertensive Rats
The endothelial receptor for oxidized LDL (oxLDL), LOX-1 is involved in hypertensive damage. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide. Cyp1a1ren-2 rats exhibit increased ET-1 levels and are used as a model of malignant hypertension. We analyzed the effects of ET-1 on LOX-1 expression in rat glomerular endothelial cells (RGEC) and in hypertensive Sprague Dawley (SD, angiotensin II infusion by osmotic mini-pump) and cyp1a1ren-2 rats. RGEC were exposed to ET-1 (up to 100 nmol/l) for one hour. LOX-1 mRNA (TaqMan) and protein expression (Western blotting) were determined in RGEC (n=4, mean±SEM, relative to beta-actin). The mRNA of LOX 1 and other genes involved in LOX-1 regulation (Table 1⇓) were investigated in kidneys and left ventricles of SD and cyp1a1ren-2 rats. In cyp1a1ren-2 rats, LOX-1 expression was additionally determined in Aorta descendens and Vena cava. Up-take of oxLDL into RGEC was quantified with fluorescent-labeled oxLDL and normalized to protein contents. Results: Pre-incubation with ET-1 increased LOX-1 mRNA and protein concentration-dependently. It was mediated via the ETB receptor as pre-incubation with BQ-788 abolished the increase in LOX-1 expression and prevented the ET-1-mediated increase in oxLDL uptake in RGEC. LOX-1 mRNA expression was significantly enhanced in kidneys and left ventricles of SD and moreover of A. descendens (8.2-fold) and V. cava (3.3-fold) of cyp1a1ren-2 animals. Interestingly, AT1 was significantly down-regulated, whereas ETA and B, and eNOS were differentially regulated in both tissues of SD rats. ET-1 up-regulates LOX-1 expression and up-take of oxLDL into RGEC via an ETB-dependent pathway. Tissue-specific enhancement of LOX-1 mRNA expression was observed in kidneys and left ventricles of hypertensive SD and cyp1a1ren-2 rats. ET-1-mediated up-regulation of LOX-1 expression may contribute to the development of hypertension and endothelial dysfunction.