Endothelin/Endothelium Endothelin-1 Increases Glomerular Permeability and Inflammation Independent of Blood Pressure in the Rat Mohamed A. Saleh, Erika I. Boesen, Jennifer S. Pollock, Virginia J. Savin, David M. Pollock Abstract—Endothelin (ET) 1 is a potent vasoactive peptide implicated in the pathogenesis of hypertension and renal disease. The aim of the current study was to test the hypotheses that ET-1 increases albumin permeability of glomeruli isolated from normal rats and that chronic ET-1 infusion will increase glomerular permeability and inflammation independent of blood pressure. Glomerular permeability to albumin was determined from the change in glomerular volume induced by exposing isolated glomeruli to oncotic gradients. Incubation of glomeruli taken from normal rats with ET-1 at a concentration that did not produce direct glomerular contraction (1 nmol/L) significantly increased glomerular permeability to albumin, reaching a maximum after 4 hours. Chronic ET-1 infusion for 2 weeks in Sprague-Dawley rats significantly increased glomerular permeability to albumin and nephrin excretion rate, effects that were attenuated in rats given an ET A receptor antagonist (ABT-627, 5 mg/kg per day). Urinary protein and albumin excretion and mean arterial pressure (telemetry) were not changed by ET-1 infusion. Acute incubation of glomeruli isolated from ET-1–infused rats with the selective ET A antagonist significantly reduced glomerular permeability to albumin, an effect not observed with acute treatment with a selective ET B antagonist. Chronic ET-1 infusion increased glomerular and plasma soluble intercellular adhesion molecule 1 and monocyte chemoattractant protein 1 and elevated the number of macrophages and lymphocytes in renal cortices (ED-1 and CD3-positive staining, respectively). These effects were all attenuated in rats given an ET A selective antagonist. These data support the hypothesis that ET-1 directly increases glomerular permeability to albumin and renal inflammation via ET A receptor activation independent of changes in arterial pressure. (Hypertension. 2010;56:942-949.) Key Words: intercellular adhesion molecule  monocyte chemotactic protein  macrophage  kidney  rat A t a physiological level, endothelin (ET) 1 plays an important role in the control of fluid-volume balance and blood pressure. Specifically, ET-1 promotes diuresis and natriuresis within the collecting duct and action through ET B receptors. 1 Systemically, ET B receptors clear ET-1 from the circulation and protect against ET A receptor– dependent va- soconstriction, cell proliferation, matrix accumulation, and inflammation. 2 Recent clinical studies have suggested that ET A antagonists may be a useful therapeutic approach for proteinuric renal disease, 3 but the precise mechanism of action is not known. ET A receptors are responsible for a wide range of effects in the kidney including vasoconstriction of renal cortical vessels, mesangial cell contraction and prolif- eration, stimulation of extracellular matrix production, and inflammation. 4 The ET system has been implicated in a variety of renal diseases including chronic proteinuric disor- ders, such as diabetes mellitus, hypertension, and glomerulo- nephritis. Overexpression of ET-1 in the kidney causes renal inflammation and fibrosis. 5 This role is supported by the finding that ET A or ET A/B antagonists attenuate development and progression of renal disease in models of these disorders. Proteinuria and albuminuria represent early signs of glo- merular injury, and their presence predicts not only an elevated risk for nephropathy but also cardiovascular disease in general. 6 The mechanistic pathways of albuminuria in chronic kidney disease have not been resolved. A recent phase III clinical trial in patients with diabetic nephropathy demonstrated that avosentan, a modestly selective ET A an- tagonist, decreased urinary albumin excretion rate after 12 weeks of treatment. 7 This benefit occurred although nearly all of the subjects in this trial were receiving treatment with angiotensin receptor blockers and angiotensin-converting en- zyme inhibitors, indicating an independent antiproteinuric effect of ET receptor antagonism. However, the main adverse effect of the new class of drugs was peripheral edema, especially at high dosages of avosentan. Little is known about the specific mechanisms of ET-1 action in chronic kidney disease, and many of the beneficial effects of ET antagonists have not been distinguished from their blood pressure– lowering effect. Chemokines such as monocyte chemoattractant protein-1 (MCP-1) and soluble (s) intercellular adhesion molecule-1 Received May 13, 2010; first decision June 1, 2010; revision accepted August 9, 2010. From the Vascular Biology Center (M.A.S., E.I.B., J.S.P., D.M.P.), Department of Pharmacology and Toxicology (M.A.S., J.S.P., D.M.P.), Department of Physiology (E.I.B., D.M.P.), and Department of Surgery (D.M.P.), Medical College of Georgia, Augusta, Ga; Department of Medicine (V.J.S.), Kansas City Veteran’s Administration Medical Center, Kansas City, Mo. Correspondence to David M. Pollock, Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd, Augusta, GA 30912-2500. E-mail dpollock@mcg.edu © 2010 American Heart Association, Inc. 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