Distinct Actions of Endothelin A-Selective Versus Combined Endothelin A/B Receptor Antagonists in Early Diabetic Kidney Disease

• DOI: 10.1124/jpet.111.178988
• Publication Date: 2011-04-07T02:43:58Z
• Authors: Mohamed A. Saleh; Jennifer S. Pollock; David M. Pollock
• Keywords: Male; 0301 basic medicine; Sulfonamides; Pyrrolidines; Endothelin A Receptor Antagonists; Stereoisomerism; Receptor, Endothelin A; Receptor, Endothelin B; Diabetes Mellitus, Experimental; Endothelin B Receptor Antagonists; Rats; 3. Good health; Rats, Sprague-Dawley; Random Allocation; 03 medical and health sciences; Atrasentan; Animals; Diabetic Nephropathies

Selective endothelin A (ET_A) and combined ET_A ET_B receptor antagonists are being investigated for use in treating diabetic nephropathy. However, the receptor-specific mechanisms responsible producing potential benefits have not been discerned. Thus, we determined actions of receptors on measures glomerular function renal inflammation early stages injury rats through selective antagonists. Six weeks after streptozotocin (STZ)-induced hyperglycemia, were given 2<i>R</i>-(4-methoxyphenyl)-4<i>S</i>-(1,3-benzodioxol-5-yl)-1-(<i>N</i>,<i>N</i>-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3<i>R</i>-carboxylic acid (ABT-627) (5 mg/kg/day), a antagonist; (2<i>R</i>,3<i>R</i>,4<i>S</i>)-4-(benzo[<i>d</i>][1,3]dioxol-5-yl)-2-(3-fluoro-4-methoxyphenyl)-1-(2-(<i>N</i>-propylpentylsulfonamido)ethyl)pyrrolidine-3-carboxylic hydrochloride (A-182086) (10 ET_A/B or vehicle 1 week. Sham controls received STZ (saline). Hyperglycemia led to significant proteinuria, increased permeability albumin (<i>P</i>_alb), nephrinuria, an increase total matrix metalloprotease (MMP) transforming growth factor-β1 (TGF-β1) activities glomeruli. Plasma soluble intercellular adhesion molecule-1 (sICAM-1) monocyte chemoattractant protein-1 (MCP-1) elevated 7 hyperglycemia. Daily administration both ABT-627 A-182086 week significantly attenuated <i>P</i>_alb, MMP TGF-β1 activity. sICAM-1 MCP-1 expression was with ABT-627, but A-182086, treatment. In summary, reduced proteinuria restored filtration barrier component integrity, only ET_A-selective blockade had anti-inflammatory antifibrotic effects. We conclude that more likely be preferred treatment kidney disease.