Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist

Aims: Diabetes is known to cause alteration of the endothelin (ET) system. We have previously demonstrated that ETs regulate augmented production of extracellular matrix proteins causing structural alterations in type 1 diabetes. Here we investigated the effects of macitentan, an orally-active, tissue-targeting dual ET receptor antagonist on chronic complications in type 2 diabetes. Main methods: db/db mice and their age- and sex-matched controls were examined after 2 and 4 months of diabetes. Groups of diabetic animals were treated with oral macitentan (25 mg/kg/day). The animals were monitored with respect to body weight and blood glucose. Urine analyses were performed for albumin. Cardiac hemodynamic studies were carried out. Renal, cardiac and retinal tissues were analyzed for ET-1, transforming growth factor-beta 1 (TGF-beta 1), vascular endothelial growth factor (VEGF), fibronectin (FN), extradomain B containing FN (EDB+FN) and collagen alpha-I (IV) mRNA. Cardiac atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured. Protein expressions were measured by ELISA and Western blot. Microscopic analyses were performed in the kidneys. Key findings: Diabetic animals showed hyperglycemia, increased urinary albumin and augmented serum creatinine levels. Diabetes caused increased renal, cardiac and retinal ET-1, TGF-beta 1, VEGF, FN, EDB+FN, collagen alpha-I(IV) mRNA expression along with increased FN and collagen protein and NF-kappa B activation. Diabetic mice also demonstrated mesangial expansion, cardiac dysfunction and increased expression of ANP and BNP. Treatment with macitentan attenuated such abnormalities. Significance: These experiments confirmed that ET system plays a significant role in the pathogenesis of chronic complications in type 2 diabetes. Such diabetes induced changes can be reduced macitentan therapy. (c) 2012 Elsevier Inc. All rights reserved.