title: Prograf produces a molecular environment favoring antifibrosis, an effect reversed by the addition of rapamune.
abstract: Rapamune, an inhibitor of the mammalian target of rapamycin, exhibits antiproliferative actions and is increasingly used as adjuvant therapy with calcineurin inhibitors. This study investigated the effect of Rapamune on functional and molecular markers in a rat model of calcineurin inhibitor-induced graft dysfunction. Prograf (6 mg), with or without addition of Rapamune (1 mg), was administered to salt-depleted male rats (n = 6/group). Urinary protein excretion and serum creatinine were measured. Rats were culled at 28 days, and messenger RNA expression of TGF-beta, MMP-2, MMP-9, TIMP-1, and collagen III was evaluated with reverse transcriptase polymerase chain reaction. Serum creatinine increased with Prograf (P = .01), but not Rapamune (P = .69) treatment, compared to controls at 28 days. The combination of Rapamune and Prograf produced a rise in serum creatinine at 7 (P = .007) and 14 (P = .01) days, but this was not observed at later time points. Urinary protein excretion was unaltered by any drug or combination. While confirming a synergistic effect of Rapamune and calcineurin inhibitors on renal function, these results suggest that sole therapy with Prograf produces inhibition of fibrotic gene expression. Rapamune alone has no deleterious effect on gene expression but addition of Rapamune cancels out the beneficial effects of Prograf.
authors.affiliation: University of Leicetser, Transplant Surgery Group, Leicester General Hospital, Leicetser, UK. nicholasbrook@fastmail.fm
authors.forename: N R
authors.initials: NR
authors.lastname: Brook
authors.forename: J R
authors.initials: JR
authors.lastname: Waller
authors.forename: G R
authors.initials: GR
authors.lastname: Bicknell
authors.forename: M L
authors.initials: ML
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004039:Diet, Sodium-Restricted; D005355:Fibrosis / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D020123:Sirolimus; D016559:Tacrolimus