Mycophenolate mofetil attenuates renal ischemia/reperfusion injury.
Immunosuppressive agents may have an impact on ischemia/reperfusion (I/R) injury. The immunosuppressant mycophenolate mofetil (MMF) presents properties that can attenuate such injury. This study investigated the effects of MMF on renal I/R injury. Male Wistar rats received MMF (20 mg/kg per d) or vehicle by gavage beginning 2 d before ischemia and maintained during the entire study. Ischemic injury was induced by bilateral renal arteries occlusion for 60 min. Control rats received MMF and underwent sham operation. At days 1, 2, and 14, post-ischemia renal function was assessed and kidneys were removed for histologic and immunohistochemical studies. MMF given to nonischemic rats did not alter renal function. There was no functional protection at 24 h post-ischemia with MMF. At 2 d, post-ischemia rats pretreated with MMF presented higher inulin clearance compared with untreated rats (0.42 +/- 0.04 versus 0.15 +/- 0.02 ml/min per 100 g; P < 0.001) and attenuated renal blood flow decrease (5.23 +/- 0.28 versus 3.24 +/- 0.37 ml/min; P < 0.01). The immunostaining for intercellular adhesion molecule-1 (ICAM-1) was less intense in rats pretreated with MMF. These rats also presented an earlier decreased infiltrating macrophages/lymphocytes and cell proliferation at day 1 post-ischemia. The functional and immunohistochemical analyses performed at day 14 post-ischemia returned to values similar to controls in both groups of rats. To determine whether mycophenolic acid (MPA) could induce cytoprotection, the effects of MPA on normoxic and hypoxic/reoxygenated (H/R) isolated tubule suspensions were also investigated. MPA was not deleterious to normoxic tubules and it was not protective against H/R tubules. In conclusion, pretreatment with MMF attenuates I/R injury in rats and does not limit the recovery from ischemia. The protective effect of MMF by reducing inflammation precedes the hemodynamic changes and tubular injury.
Ventura
Carlucci Gualberto
CG
Department of Nephrology, Laboratório de Investigação Médica 12, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Coimbra
Terezila Machado
TM
de Campos
Silvia Bernardete
SB
de Castro
Isac
I
Yu
Luis
L
Seguro
Antonio Carlos
AC
D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D053331:Ectodysplasins; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007511:Ischemia / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*
D053331:Ectodysplasins; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D018809:Proliferating Cell Nuclear Antigen; D018799:Intercellular Adhesion Molecule-1; D007770:L-Lactate Dehydrogenase; D009173:Mycophenolic Acid