Synergistic effects of mycophenolate mofetil and losartan in a model of chronic cyclosporine nephropathy.
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.
Yang
Chul Woo
CW
Cell Death Disease Research Center, Division of Nephrology, Department of Internal Medicine, Kangnam St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Ahn
Hee Jong
HJ
Kim
Wan Young
WY
Li
Can
C
Jung
Ju Young
JY
Yoon
Sun Ae
SA
Kim
Yong Soo
YS
Cha
Jung Ho
JH
Kim
Jin
J
Bang
Byung Kee
BK
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
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