title: The calcimimetic calindol prevents high phosphate-induced vascular calcification by upregulating matrix GLA protein.
abstract: BACKGROUND
  High serum phosphate (Pi) levels represent a major issue in dialysis patients, because associate with secondary hyperparathyroidism, vascular calcification (VC), and cardiovascular outcomes. In this population, calcimimetics are used to control secondary hyperparathyroidism, hyperphosphatemia, and, more recently, to delay the progression of VC. The aim of this in vitro study was to investigate the direct effects of the calcimimetic calindol on the progression of high Pi-induced VC.
  
  
  METHODS
  Rat vascular smooth muscle cells (VSMCs) were incubated with high Pi concentrations, and the effects of calindol were investigated on vascular calcium deposition and VSMC osteoblastic differentiation.
  
  
  RESULTS
  Calindol inhibited calcium deposition concentration-dependently with a maximal inhibition of 64.0 ± 5.2% achieved at 100 nM. Furthermore, calindol was able to partially prevent the high Pi-induced bone morphogenic protein 2 (BMP-2) expression upregulation (32.4 ± 4.6% of inhibition; p < 0.01). Interestingly, the pretreatment with calindol enhanced the matrix Gla protein (MGP) gene expression significantly, compared to high Pi-treated cells (40.2 ± 6.6% of increase, p < 0.01).
  
  
  CONCLUSIONS
  In conclusion, we demonstrated that the calcimimetic calindol prevents high Pi-induced VC by affecting osteoblastic differentiation in vitro. In particular, the inhibitory effect of calindol on VC is probably due to its stimulatory role on the calcium-sensing receptor, leading to an increase in the synthesis of MGP by VSMCs.
authors.affiliation: Renal Division and Laboratory of Experimental Nephrology, Dipartimento di Scienze della Salute, Università di Milano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ciceri
authors.forename: Francesca
authors.initials: F
authors.lastname: Elli
authors.forename: Irene
authors.initials: I
authors.lastname: Brenna
authors.forename: Elisa
authors.initials: E
authors.lastname: Volpi
authors.forename: Diego
authors.initials: D
authors.lastname: Brancaccio
authors.forename: Mario
authors.initials: M
authors.lastname: Cozzolino
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000187:drug effects*; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009281:Naphthalenes / Q000627:therapeutic use*; D010710:Phosphates / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D061205:Vascular Calcification / Q000517:prevention & control*; D000094963:Axl Receptor Tyrosine Kinase; D000097568:Matrix Gla Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D002118:Calcium; D002135:Calcium-Binding Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D016326:Extracellular Matrix Proteins; D007211:Indoles; D009281:Naphthalenes; D010710:Phosphates; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000097568:Matrix Gla Protein; C506457:(R)-2-(1-(1-naphthyl)ethyl-aminom-ethyl)indole; C525720:Bmp2 protein, rat; C493717:Runx2 protein, rat