title: Effects of MCP-1 inhibition by bindarit therapy in a rat model of polycystic kidney disease.
abstract: OBJECTIVE
  Experimental and clinical evidence suggested that monocyte chemoattractant protein-1 (MCP-1/CCL2) has a role in the development of interstitial inflammation and renal failure in polycystic kidney disease (PKD). We investigated whether bindarit, an inhibitor of MCP-1/CCL2 synthesis, could influence the evolution of PKD in PCK rats.
  
  
  METHODS
  PCK rats were treated from 5 to 15 weeks of age with vehicle or bindarit. Sprague-Dawley rats served as control. For in vitro studies, murine podocytes were exposed to albumin with or without bindarit.
  
  
  RESULTS
  MCP-1 mRNA was upregulated in the kidney of PCK rats and reduced by bindarit. Treatment limited overexpression of MCP-1 protein by epithelial cells of dilated tubules and cysts, and interstitial inflammatory cells. Excessive renal accumulation of monocytes/macrophages was lowered by bindarit by 41%. Serum creatinine slightly increased in PCK rats on vehicle and was similar to controls after bindarit. Kidney and liver cysts were not affected by treatment. Bindarit significantly reduced progressive proteinuria of PCK rats. The antiproteinuric effect was associated with the restoration of the defective nephrin expression in podocytes of PCK rats. Bindarit limited podocyte foot process effacement and ameliorated slit diaphragm frequency. In cultured podocytes, bindarit reduced MCP-1 production in response to albumin and inhibited albumin-induced cytoskeletal remodeling and cell migration.
  
  
  CONCLUSIONS
  This study showed that although bindarit did not prevent renal cyst growth, it limited interstitial inflammation and renal dysfunction and reduced proteinuria in PKD. Thus, bindarit could be considered a therapeutic intervention complementary to therapies specifically acting to block renal cyst growth.
authors.forename: Carlamaria
authors.initials: C
authors.lastname: Zoja
authors.forename: Daniela
authors.initials: D
authors.lastname: Corna
authors.forename: Monica
authors.initials: M
authors.lastname: Locatelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Rottoli
authors.forename: Anna
authors.initials: A
authors.lastname: Pezzotta
authors.forename: Marina
authors.initials: M
authors.lastname: Morigi
authors.forename: Cristina
authors.initials: C
authors.lastname: Zanchi
authors.forename: Simona
authors.initials: S
authors.lastname: Buelli
authors.forename: Angelo
authors.initials: A
authors.lastname: Guglielmotti
authors.forename: Norberto
authors.initials: N
authors.lastname: Perico
authors.forename: Andrea
authors.initials: A
authors.lastname: Remuzzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D007191:Indazoles / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011422:Propionates / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007191:Indazoles; D011422:Propionates; D012333:RNA, Messenger; C079489:bindarit