Trimetazidine reduces early and long-term effects of experimental renal warm ischemia: a dose effect study.
OBJECTIVE
Renal ischemia reperfusion (IR) injury (IRI) is an important mechanism of acute renal failure (ARF) and a crucial factor of tissue damage during vascular surgery. IR may lead to tissue destruction and influence the early and long-term outcome of organs. The anti-anginal medication trimetazidine (TMZ) is a drug, the protective effects of which have been already assessed during cold preservation and warm ischemia (WI). The objective of this dose-effect study was to assess the role of TMZ in severe renal WI model.


METHODS
We have used an established WI pig kidney model associated with a uninephrectomy condition and studied the dose-dependent role of TMZ (1, 5, and 10 mg/Kg, i.v. for 24 hours before WI) against deleterious effects of WI (60 minutes of WI followed by reperfusion) compared with sham-operated (control) and uninephrectomized animals (unif). Direct effect of TMZ was determined using different variables: renal function (creatinine clearance; C(cr)) and indirectly, the consequences on inflammation (cells infiltration), rate of apoptosis, fibrosis development, and renal epithelial cells change into myofibroblast, which defined epithelial to mesenchymal transition (alpha-smooth muscle actin [alpha-SMA] and vimentin expression).


RESULTS
TMZ (5 or 10 mg/Kg) significantly increased C(cr) and reduced the inflammatory response prevalent in ischemic kidney injury and rate of apoptosis expression. In addition, the limitation of initial IRI was correlated with an earlier and greater expression of hypoxia-inducible transcription factor-1alpha (HIF-1alpha), which is a hypoxia marker during kidney regeneration. A reduction of the tubulointerstitial development of fibrosis and a limitation of the alpha-smooth muscle actin expression (alpha-SMA) was observed with TMZ treatment. At 3 months, vimentin expression was increased in WI groups without TMZ or low TMZ dose treatment compared with 5 or 10 mg/Kg treated groups.


CONCLUSIONS
Collectively, these data suggest that TMZ made the warm ischemic kidneys more resistant to the deleterious impact of a single episode of IR and could have a role in preserving the ischemic kidney from long-term damage.
Cau
Jerome
J
Université de Poitiers, Poitiers, France.
Favreau
Frederic
F
Tillement
Jean Paul
JP
Lerman
Lilach O
LO
Hauet
Thierry
T
Goujon
Jean Michel
JM
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D009392:Nephrectomy; D012079:Renal Circulation / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D013552:Swine; D014022:Tissue Survival / Q000187:drug effects; D014292:Trimetazidine / Q000494:pharmacology* / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014746:Vimentin / Q000032:analysis; D052096:Warm Ischemia / Q000009:adverse effects*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014665:Vasodilator Agents; D014746:Vimentin; D014292:Trimetazidine