title: Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist.
abstract: OBJECTIVE
  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.
  
  
  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 (25mg/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-β1 (TGF-β1), vascular endothelial growth factor (VEGF), fibronectin (FN), extradomain B containing FN (EDB(+)FN) and collagen α-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.
  
  
  RESULTS
  Diabetic animals showed hyperglycemia, increased urinary albumin and augmented serum creatinine levels. Diabetes caused increased renal, cardiac and retinal ET-1, TGF-β1, VEGF, FN, EDB(+)FN, collagen α-I(IV) mRNA expression along with increased FN and collagen protein and NF-κB activation. Diabetic mice also demonstrated mesangial expansion, cardiac dysfunction and increased expression of ANP and BNP. Treatment with macitentan attenuated such abnormalities.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dept. of Pathology, University of Western Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Sen
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.forename: B
authors.initials: B
authors.lastname: Feng
authors.forename: M
authors.initials: M
authors.lastname: Iglarz
authors.forename: S
authors.initials: S
authors.lastname: Chakrabarti
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan