The effect of mycophenolate mofetil and polyphenolic bioflavonoids on renal ischemia reperfusion injury and repair.
OBJECTIVE
Chronic renal allograft nephropathy is associated with both immune and ischemic injury which may act synergistically to promote an inflammatory response. The immunosuppressant mycophenolic acid and the polyphenolic agents curcumin and quercetin possess properties that might ameliorate such injury. We studied the effects of these agents in models of ischemic renal injury and skin allograft rejection.


METHODS
Ischemic acute tubular necrosis was produced in rats by renal pedicle occlusion with contralateral nephrectomy. Animals were treated with mycophenolic acid, quercetin and curcumin, or a combination of agents. Animals were killed on days 2 and 7 after operation and tissue samples were collected. Renal tubular apoptosis and cellular proliferation were assessed by immunohistochemistry. Expression of the cytokines RANTES and AIF were evaluated by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR).


RESULTS
Treatment with the polyphenolic compounds alone or in combination with mycophenolic acid was associated with less tubular damage, attenuation of renal inflammation, and prolongation of skin graft survival. A combination of agents decreased serum creatinine on day 2 from 4.5 to 0.9 mg./dl. (p< or =0.01) and at day 7 from 3.8 to 0.6 mg./dl. (p< or =0.01). Treatment with the polyphenolic compounds inhibited apoptosis at day 2. By RT-PCR, RANTES and AIF were detected at high levels on days 2 and 7. Treatment with these agents alone or in combination strongly attenuated this increased expression.


CONCLUSIONS
The combination of mycophenolic acid with curcumin and quercetin reduces renal injury and facilitates repair. These agents may have a role in therapeutic regimens that are both immunosuppressive and renoprotective.
Jones
E A
EA
Division of Urology, Harbor-UCLA Medical Center, Torrance, California 90509, USA.
Shoskes
D A
DA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D003474:Curcumin / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000517:prevention & control*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007511:Ischemia / Q000517:prevention & control*; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009393:Nephritis / Q000517:prevention & control*; D011794:Quercetin / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016038:Skin Transplantation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018946:Chemokine CCL5; D007166:Immunosuppressive Agents; D011794:Quercetin; D009173:Mycophenolic Acid; D003474:Curcumin