Effects of mycophenolate mofetil on acute ischaemia-reperfusion injury in rats and its consequences in the long term.
BACKGROUND
Renal ischaemia-reperfusion injury (IRI) acutely decreases glomerular filtration rate (GFR) and impairs kidney function in the long term. Pre-treatment with chaetomellic acid (KM), an inhibitor of membrane-bound Ha-Ras, has demonstrated beneficial effects on acute renal ischaemia.


METHODS
We tested whether mycophenolate mofetil (MMF, 20 mg/day for 4 days before IRI), an immunosuppressor with anti-inflammatory properties, improved renal outcome in uninephrectomized rats after IRI (45 min of renal ischaemia), alone or in combination with KM.


RESULTS
One day after ischaemia, GFR was markedly depressed in untreated rats (-75% vs. normal rats, P < 0.001), and pre-treatment with MMF did not modify this fall (-75%, P < 0.001 vs. normal). KM (0.23 microg/kg before IRI) greatly prevented GFR loss (-39% vs. normal, P < 0.05), but its action was not further improved by the combined administration with MMF (GFR, -45% vs. normal, P < 0.05). MMF significantly reduced ICAM-1 expression and monocyte recruitment (P < 0.05 vs. untreated rats); nevertheless, renal histology of MMF rats was similar to that of untreated rats. Additional rats were examined 6 months after IRI: untreated rats with IRI showed reduced renal function (-42% vs. normal, P < 0.01) and proteinuria (P < 0.001 vs. normal); rats pre-treated with MMF showed a similar pattern, whereas rats treated with KM before IRI presented a better GFR (-20% vs. normal, not significant) and near-normal values of proteinuria. The combination of KM + MMF gained the same results.


CONCLUSIONS
Pre-treatment with MMF before IRI does not confer functional or morphological protection to the kidney, despite the reduced expression of some inflammatory markers. The combination of MMF + KM does not offer additional advantages to solitary KM treatment.
Sabbatini
Massimo
M
Department of Systematic Pathology, University Federico II, Naples Italy. sabbatin@unina.it
Uccello
Francesco
F
Serio
Vittorio
V
Troncone
Giancarlo
G
Varone
Valeria
V
Andreucci
Michele
M
Faga
Teresa
T
Pisani
Antonio
A
D000818:Animals; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D008297:Male; D008298:Maleates / Q000627:therapeutic use; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D018631:ras Proteins / Q000037:antagonists & inhibitors
D007166:Immunosuppressive Agents; D008298:Maleates; D018799:Intercellular Adhesion Molecule-1; C080569:chaetomellic acid A; D018631:ras Proteins; D009173:Mycophenolic Acid