title: Antifibrotic, nephroprotective effects of paricalcitol versus calcitriol on top of ACE-inhibitor therapy in the COL4A3 knockout mouse model for progressive renal fibrosis.
abstract: BACKGROUND
  The COL4A3-/- mouse serves as animal model for progressive renal fibrosis. Using this animal model, the present study investigates the nephroprotective effects of Paricalcitol versus Calcitriol alone and on top of ACE-inhibitor therapy.
  
  
  METHODS
  Eighty six mice were divided into six groups: (PC) with Paricalcitol 0.1 mcg/kg, (CA) Calcitriol 0.03 mcg/kg (dose equipotent), (PLAC) vehicle 0.1 mL i.p. five times per week, (ACE + PC) Paricalcitol plus Ramipril, (ACE + CA) Calcitriol plus Ramipril and (ACE + PLAC) vehicle plus Ramipril 10 mg/kg/day p.o. ACE therapy started pre-emptively in Week 4, PC/CA therapy was initiated in 6-week-old animals with ongoing renal fibrosis and lasted for 8 weeks. Four to six animals were sacrificed after 9.5 weeks and kidneys were further investigated using histological, immunohistological and Western-blot techniques. Survival until end-stage renal failure was determined in the remaining animals.
  
  
  RESULTS
  PC, but not CA, prolonged lifespan until renal failure by 13% compared with untreated controls (P = 0.069). ACE-inhibition prolonged lifespan by >50%. Added on top of ACE inhibition, ACE + PC (but not ACE + CA) even further prolonged lifespan by additional 18.0% (P < 0.01 versus ACE + PLAC) and improved renal function (blood urea nitrogen; P < 0.05 versus ACE + CA). Accumulation of extracellular matrix and renal scarring was decreased in PC and ACE + PC-treated mice.
  
  
  CONCLUSIONS
  The present study demonstrated a substantial nephroprotective and antifibrotic effect of the vitamin D-receptor activator Paricalcitol on top of early ACE inhibition in the COL4A3-/- model of progressive kidney fibrosis. The synergistic effect of Paricalcitol on top of RAAS-blockade might as well be valuable in other chronic kidney diseases.
authors.affiliation: Department of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Rubel
authors.forename: Johanna
authors.initials: J
authors.lastname: Stock
authors.forename: Ayse
authors.initials: A
authors.lastname: Ciner
authors.forename: Henrik
authors.initials: H
authors.lastname: Hiller
authors.forename: Rainer
authors.initials: R
authors.lastname: Girgert
authors.forename: Gerhard-Anton
authors.initials: GA
authors.lastname: Müller
authors.forename: Oliver
authors.initials: O
authors.lastname: Gross
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001324:Autoantigens / Q000502:physiology*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D002117:Calcitriol / Q000627:therapeutic use*; D024141:Collagen Type IV / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004872:Ergocalciferols / Q000627:therapeutic use*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017257:Ramipril / Q000627:therapeutic use; D018167:Receptors, Calcitriol / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001324:Autoantigens; D050071:Bone Density Conservation Agents; D024141:Collagen Type IV; D016207:Cytokines; D004872:Ergocalciferols; D018167:Receptors, Calcitriol; C057112:type IV collagen alpha3 chain; C084656:paricalcitol; D002117:Calcitriol; D017257:Ramipril
keywords: Alport syndrome; collagen; fibrosis; nephroprotection; renal insufficiency