title: Angiotensin-II and rosuvastatin influence matrix remodeling in human mesangial cells via metalloproteinase modulation.
abstract: OBJECTIVE
  Persistent inflammation and oxidative stress influence the progression of diabetic nephropathy. Metalloproteinases (MMPs) participate in extracellular matrix remodeling. Statins show favorable anti-inflammatory effects in chronic kidney disease. We evaluated the effect of rosuvastatin on inflammatory and pro-fibrotic responses due to exposure to different glucose or free fatty acid (FFA) concentrations.
  
  
  METHODS
  Human mesangial cells (HMCs) grown at 5.5 (normal glucose) or 22 mmol/l (high glucose) glucose or exposed to FFA were treated with angiotensin-II in the presence or absence of rosuvastatin. We measured MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 expression and activity, and quantified the fibrotic factors transforming growth factor-β1 (TGF-β1), fibronectin, and collagen IV.
  
  
  RESULTS
  At normal glucose, angiotensin-II induced a dose-dependent downregulation of MMP-2; rosuvastatin reversed this effect. On the contrary, TIMP-2 and MMP-9 were upregulated by angiotensin-II and downregulated by rosuvastatin; the effects on TIMP-1 were negligible. Some of the angiotensin-II effects were potentiated in the presence of high glucose and FFA; under both conditions, rosuvastatin was able to reverse these effects. MMP-2 and MMP-9 activity followed the same trend of expression, with rosuvastatin able to upregulate MMP-2 activity. The modulation of the MMP/TIMP system was paralleled by an increase in TGF-β1, fibronectin, and collagen-IV; all were reduced by rosuvastatin treatment. Silencing the MMP-2 gene confirmed its role in modulating some of these angiotensin-II effects.
  
  
  CONCLUSIONS
  Angiotensin-II induces a pro-fibrotic response in HMCs mainly via a dysregulation of the MMP-2/TIMP-2 pattern. This effect, partially amplified in the presence of high glucose and FFA, is reversed by rosuvastatin, suggesting another potential therapeutic application for this 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor.
authors: Department of Internal Medicine, University of Pisa, Pisa, Italy. anna.solini@med.unipi.it
authors: Anna
authors: A
authors: Solini
authors: Chiara
authors: C
authors: Rossi
authors: Eleonora
authors: E
authors: Santini
authors: Stephanie
authors: S
authors: Madec
authors: Antonio
authors: A
authors: Salvati
authors: Ele
authors: E
authors: Ferrannini
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005355:Fibrosis; D005464:Fluorobenzenes / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D045726:Metalloproteases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013449:Sulfonamides; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D019716:Tissue Inhibitor of Metalloproteinase-2; D000068718:Rosuvastatin Calcium; D045726:Metalloproteases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D005947:Glucose