title: Synergistic effects of mycophenolate mofetil and losartan in a model of chronic cyclosporine nephropathy.
abstract: BACKGROUND
  Combined treatments of mycophenolate mofetil (MMF) and losartan (LSRT) have synergistic effects on various renal diseases through their hemodynamic and anti-inflammatory effects. This study investigated whether MMF treatment is effective in inhibiting inflammatory processes in chronic cyclosporine A (CsA) nephrotoxicity, and whether combined treatment using MMF and LSRT affords superior protection compared with the respective monotherapies.
  
  
  METHODS
  Rats on a low-salt diet were given vehicle (VH group, olive oil, 1 mg/kg per day), CsA (15 mg/kg per day), CsA and LSRT (CsA+LSRT group, 100 mg/L per day), CsA and MMF (CsA+MMF group; 40 mg/kg per day), or CsA, LSRT and MMF (CsA+LSRT MMF group). Control groups received each drug without CsA treatment. Renal function, histologic parameters (arteriolopathy, tubulointerstitial fibrosis, and inflammatory cell infiltration), and mediators of CsA-induced nephrotoxicity (angiotensin-II, osteopontin, and transforming growth factor [TGF]-beta1) were studied.
  
  
  RESULTS
  The CsA-treated rats showed decreased renal function and increased histologic parameters compared with the VH-treated rats. The CsA+MMF treatment significantly improved renal function and histopathologic parameters compared with the CsA group, and combined treatment with MMF and LSRT further improved those parameters compared with the CsA+LSRT and CsA+MMF groups. At a molecular level, increased expression of angiotensin II protein, osteopontin, and TGF-beta1 mRNAs in the CsA group were significantly decreased with MMF, and further decrease was observed with the combined treatment using MMF and LSRT.
  
  
  CONCLUSIONS
  MMF treatment decreases CsA-induced nephrotoxicity, and combined treatment with LSRT has a synergistic effect in preventing chronic CsA nephrotoxicity.
authors.affiliation: Cell Death Disease Research Center, Division of Nephrology, Department of Internal Medicine, Kangnam St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
authors.forename: Hee Jong
authors.initials: HJ
authors.lastname: Ahn
authors.forename: Wan Young
authors.initials: WY
authors.lastname: Kim
authors.forename: Can
authors.initials: C
authors.lastname: Li
authors.forename: Ju Young
authors.initials: JY
authors.lastname: Jung
authors.forename: Sun Ae
authors.initials: SA
authors.lastname: Yoon
authors.forename: Yong Soo
authors.initials: YS
authors.lastname: Kim
authors.forename: Jung Ho
authors.initials: JH
authors.lastname: Cha
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Byung Kee
authors.initials: BK
authors.lastname: Bang
mesh_terms: D000804:Angiotensin II / Q000096:biosynthesis; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001160:Arterioles / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D016572:Cyclosporine / Q000097:blood / Q000633:toxicity; D004357:Drug Synergism; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply / Q000473:pathology / Q000502:physiology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy*; D019808:Losartan / Q000494:pharmacology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D053495:Osteopontin; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
chemical_list: D000959:Antihypertensive Agents; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D000804:Angiotensin II; D016572:Cyclosporine; D009173:Mycophenolic Acid; D019808:Losartan