Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model.
Acute renal failure (ARF) is often the consequence of an ischemia-reperfusion injury (IRI) and associated with high mortality. Warm ischemia (WI) is a crucial factor of tissue damage, and tissue destruction led by ischemia-reperfusion (I/R) can impact the early and long-term functional outcome. Trimetazidine (TMZ) is an anti-ischemic drug. Previously, we already verified its protective effect on a cold-ischemic pig kidney model by directly adding TMZ into the preservation solution (Faure JP, Baumert H, Han Z, Goujon JM, Favreau F, Dutheil D, Petit I, Barriere M, Tallineau C, Tillement JP, Carretier M, Mauco G, Papadopoulos V, Hauet T. Biochem Pharmacol 66: 2241-2250, 2003; Faure JP, Petit I, Zhang K, Dutheil D, Doucet C, Favreau F, Eugene M, Goujon JM, Tillement JP, Mauco G, Vandewalle A, Hauet T. Am J Transplant 4: 495-504, 2004). In this study, we aimed to study the potential effect of TMZ pretreatment (5 mg/kg iv 24 h before WI) on the injury caused by WI for 45, 60, and 90 min and reperfusion in a WI pig kidney model. Compared with sham-operated (control) and uninephrectomized animals (UNX), TMZ pretreatment significantly reduced deleterious effects after 45 min, and particularly 60 and 90 min, of WI by improving the recovery of renal function and minimizing the inflammatory response commonly prevalent in ischemic kidney injury. Compared with controls (control group and UNX group), it was observed that 1) hypoxia-inducible factor-1 (HIF-1alpha) expression occurred earlier and with a higher intensity in the TMZ-treated groups; 2) the reduction of IRI during the first week following reperfusion was correlated with an earlier and greater expression of stathmin, which is involved in the process of tubular repair; and 3) the tubulointerstitial fibrosis was reduced, particularly after 60 and 90 min of WI. In conclusion, TMZ made the warm-ischemic kidneys more resistant to the deleterious impact of a single episode of I/R and reduced early and long-term subsequent damage.
Jayle
Christophe
C
Institut National de la Santé et de la Recherche Médicale E0324, Centre Hospitalier et Universitaire de Poitiers, Poitiers, France.
Favreau
Frederic
F
Zhang
Kequiang
K
Doucet
Carole
C
Goujon
Jean Michel
JM
Hebrard
William
W
Carretier
Michel
M
Eugene
Michel
M
Mauco
Gerard
G
Tillement
Jean Paul
JP
Hauet
Thierry
T
D000818:Animals; D015153:Blotting, Western; D003404:Creatinine / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009392:Nephrectomy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050777:Stathmin / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D034421:Sus scrofa; D013997:Time Factors; D016896:Treatment Outcome; D014292:Trimetazidine / Q000494:pharmacology / Q000627:therapeutic use*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014665:Vasodilator Agents / Q000627:therapeutic use; D052096:Warm Ischemia
D000949:Histocompatibility Antigens Class II; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D050777:Stathmin; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D003404:Creatinine; D014292:Trimetazidine