Endothelin A receptor blockade reduces diabetic renal injury via an anti-inflammatory mechanism

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 g/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-hydroxy-2-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-hydroxy-2-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-β 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-β production in diabetes and are consistent with the postulate that ET_A blockade slows progression of diabetic nephropathy via an anti-inflammatory mechanism.