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Endothelin A Receptor Blockade Reduces Diabetic Renal Injury via an Anti-Inflammatory Mechanism

Jennifer M. Sasser^*, Jennifer C. Sullivan^*, Janet L. Hobbs^*, Tatsuo Yamamoto, David M. Pollock^*, Pamela K. Carmines and Jennifer S. Pollock^*

^* Vascular Biology Center and Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia; First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; and Department of Cellular and Integrative Physiology, University of Nebraska College of Medicine, Omaha, Nebraska

Address correspondence to: Dr. Jennifer S. Pollock, Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Boulevard, Augusta, GA 30912. Phone: 706-721-8514; Fax: 706-721-9799; jpollock{at}mcg.edu

Received for publication March 7, 2006. Accepted for publication October 10, 2006.

Endothelin (ET) receptor blockade delays the progression of diabetic nephropathy; however, the mechanism of this protection is unknown. Therefore, the aim of this study was to test the hypothesis that ET_A receptor blockade attenuates superoxide production and inflammation in the kidney of diabetic rats. Diabetes was induced by streptozotocin (diabetic rats with partial insulin replacement to maintain modest hyperglycemia [HG]), and sham rats received vehicle treatments. Some rats also received the ET_A antagonist ABT-627 (sham+ABT and HG+ABT; 5 mg/kg per d; n = 8 to 10/group). During the 10-wk study, urinary microalbumin was increased in HG rats, and this effect was prevented by ET_A receptor blockade. Indices of oxidative stress, urinary excretion of thiobarbituric acid reactive substances, 8-hydroxy2-deoxyguanosine, and H₂O₂ and plasma thiobarbituric acid reactive substances were significantly greater in HG rats than in sham rats. These effects were not prevented by ABT-627. In addition, renal cortical expression of 8-hydroxy2-deoxyguanosine and NADPH oxidase subunits was not different between HG and HG+ABT rats. ET_A receptor blockade attenuated increases in macrophage infiltration and urinary excretion of TGF- and prostaglandin E₂ metabolites in HG rats. Although ABT-627 did not alleviate oxidative stress in HG rats, inflammation and production of inflammatory mediators were reduced in association with prevention of microalbuminuria. These observations indicate that ET_A receptor activation mediates renal inflammation and TGF- production in diabetes and are consistent with the postulate that ET_A blockade slows progression of diabetic nephropathy via an anti-inflammatory mechanism.

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