title: Beneficial effects of pioglitazone against cardiovascular injury are enhanced by combination with aliskiren in a rat model of diabetic nephropathy.
abstract: OBJECTIVE
  Aliskiren is the first in a new class of orally active direct renin inhibitors, approved for the treatment of hypertension. However, the efficacy of aliskiren in diabetic cardiovascular complications remains to be defined. This study aimed to test the hypothesis that aliskiren may enhance the beneficial effects of pioglitazone against cardiovascular injury associated with diabetic nephropathy.
  
  
  METHODS
  Diabetic nephropathy was induced in rats by unilateral nephrectomy followed by streptozotocin injection. Diabetic nephropathic rats were orally given vehicle, pioglitazone, aliskiren, or combined pioglitazone and aliskiren for four weeks to compare their effects on cardiovascular injury, particularly myocardial fibrosis.
  
  
  RESULTS
  Pioglitazone treatment significantly attenuated cardiac lipid peroxidation, oxidative injury and myocardial fibrosis in diabetic nephropathic rats. This was associated with up-regulation of transforming growth factor-β1 and matrix metalloproteinase-2 genes, along with down-regulation of tissue inhibitor of metalloproteinase-2 gene in cardiac tissue. The combination of aliskiren with pioglitazone exerted greater beneficial effect than monotherapy with either drug, on all the aforementioned parameters.
  
  
  CONCLUSIONS
  Our findings suggested that aliskiren enhanced the protective effects of pioglitazone against myocardial fibrosis, in experimental diabetic nephropathy. Thus, the combination of aliskiren and pioglitazone may be a potential therapeutic strategy for cardiovascular injury associated with diabetic nephropathy.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Sharkia Gov., Zagazig, Egypt. ra_elrashidy@yahoo.com
authors.forename: Rania A
authors.initials: RA
authors.lastname: Elrashidy
authors.forename: Mervat E
authors.initials: ME
authors.lastname: Asker
authors.forename: Hoda E
authors.initials: HE
authors.lastname: Mohamed
mesh_terms: D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005355:Fibrosis / Q000517:prevention & control; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009392:Nephrectomy; D018384:Oxidative Stress / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D019716:Tissue Inhibitor of Metalloproteinase-2; C446481:aliskiren; D013311:Streptozocin; D020778:Matrix Metalloproteinase 2; D000077205:Pioglitazone