This study investigated whether endothelin-1 (ET-1), a potent vasoconstrictor, which also stimulates cell proliferation, contributes to endothelial dysfunction and atherosclerosis. Apolipoprotein E (apoE)-deficient mice and C57BL͞6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ET A receptor antagonist LU135252 (50 mg͞kg͞d) for 30 wk. Systolic blood pressure, plasma lipid profile, and plasma nitrate levels were determined. In the aorta, NO-mediated endotheliumdependent relaxation, atheroma formation, ET receptorbinding capacity, and vascular ET-1 protein content were assessed. In apoE-deficient but not C57BL͞6 mice, severe atherosclerosis developed within 30 wk. Aortic ET-1 protein content (P < 0.0001) and binding capacity for ET A receptors was increased as compared with C57BL͞6 mice. In contrast, NO-mediated, endothelium-dependent relaxation to acetylcholine (56 ؎ 3 vs. 99 ؎ 2%, P < 0.0001) and plasma nitrate were reduced (57.9 ؎ 4 vs. 93 ؎ 10 mol͞liter, P < 0.01). Treatment with the ET A receptor antagonist LU135252 for 30 wk had no effect on the lipid profile or systolic blood pressure in apoE-deficient mice, but increased NO-mediated endothelium-dependent relaxation (from 56 ؎ 3 to 93 ؎ 2%, P < 0.0001 vs. untreated) as well as circulating nitrate levels (from 57.9 ؎ 4 to 80 ؎ 8.3 mol͞liter, P < 0.05). Chronic ET A receptor blockade reduced elevated tissue ET-1 levels comparable with those found in C57BL͞6 mice and inhibited atherosclerosis in the aorta by 31% without affecting plaque morphology or ET receptor-binding capacity. Thus, chronic ET A receptor blockade normalizes NO-mediated endothelial dysfunction and reduces atheroma formation independent of plasma cholesterol and blood pressure in a mouse model of human atherosclerosis. ET A receptor blockade may have therapeutic potential in patients with atherosclerosis.Diseases related to atherosclerosis such as myocardial infarction and stroke account for the majority of deaths in industrialized countries (1). In patients with cardiovascular risk factors such as hypercholesterolemia, hypertension, or aging (2, 3), endothelial dysfunction precedes the development of atherosclerosis and predisposes to the development of structural vascular changes (1, 4). The endothelium releases vasoactive mediators such as NO and endothelin (ET-1), both of which are importantly involved in the regulation of vascular tone (5, 6) and structure (7,8). Endothelial NO synthase (9-11) converts L-arginine into NO and L-citrulline (12) and its expression (13), and the release of NO (14) is reduced in atherosclerosis. In experimental atherosclerosis, inhibition of the L-arginine͞NO pathway accelerates lesion progression in hypercholesterolemic rabbits (15-17) and low density lipoprotein (LDL) receptor-deficient mice (18). Furthermore, superoxide release in atherosclerosis inactivates NO resulting in formation of peroxynitrite (19,20), the production of which is further enhanced by cholesterol (21).In patients with coronary a...

Abstract-The cause of focal-segmental glomerulosclerosis as a consequence of physiological aging, which is believed to be inexorable, is unknown. This study investigated whether inhibition of endothelin-1, a growth-promoting peptide contributing to renal injury in hypertension and diabetes, affects established glomerulosclerosis and proteinuria in the aged kidney. We also determined the role of endothelin receptors for podocyte injury in vivo and in vitro. Aged Wistar rats, a model of spontaneous age-dependent glomerulosclerosis, were treated with the orally active endothelin subtype A (ET A ) receptor antagonist darusentan, and evaluation of renal histology, renal function studies, and expression analyses were performed. In vitro experiments using puromycin aminonucleoside to induce podocyte injury investigated the role of ET A receptor signaling for apoptosis, cytoskeletal injury, and DNA synthesis. In aged Wistar rats, established glomerulosclerosis and proteinuria were reduced by Ͼ50% after 4 weeks of darusentan treatment, whereas blood pressure, glomerular filtration rate, or tubulo-interstitial renal injury remained unaffected. Improvement of structural injury in glomeruli and podocytes was accompanied by a reduction of the expression of matrix metalloproteinase-9 and p21 Cip1/WAF1 . In vitro experiments blocking ET A receptors using specific antagonists or RNA interference prevented apoptosis and structural damage to podocytes induced by puromycin aminonucleoside. In conclusion, these results support the hypothesis that endogenous endothelin contributes to glomerulosclerosis and proteinuria in the aging kidney. The results further suggest that age-dependent glomerulosclerosis is not merely a "degenerative" but a reversible process locally confined to the glomerulus involving recovery of podocytes from previous injury. Key Words: arterial presure Ⅲ nephrosclerosis Ⅲ DNA Ⅲ kidney failure Ⅲ renal artery Ⅲ expression Ⅲ kidney Ⅲ renal disease A ging represents an important factor determining onset and course of disease and has become a significant issue in view of the anticipated increase of the aging population. Aging in humans and rodents progressively impairs renal function 1,2 and structure, the latter of which is characterized by damage of podocytes and mesangial matrix, as well as capillary hypertrophy and obliteration resulting in glomerulosclerosis. 2 The exact mechanisms underlying agedependent renal injury are unknown. In otherwise healthy individuals Ն65 years of age, even in the absence of known risk factors such as hypertension or diabetes, glomerulosclerosis is frequently present. 3 Currently, Ϸ1.4% of the US total population is affected, and the incidence is expected to increase to Ͼ2% within the next 15 years. 3 Glomerulosclerosis and proteinuria involve injury of podocytes, also known as glomerular epithelial cells that maintain an intact filtration barrier and control glomerular basement membrane turnover under normal conditions. 4 -7 In addition to cell-specific changes during aging, cell c...

These data demonstrate that obesity augments prostanoid-dependent vasoconstriction and markedly increases vascular thromboxane receptor gene expression. These changes are likely to promote the development of vascular disease, hypertension and thrombosis associated with obesity.