Department of Systematic Pathology, University Federico II, Naples Italy.
Nephrol Dial Transplant. 2010 May;25(5):1443-50. doi: 10.1093/ndt/gfp710. Epub 2009 Dec 22.
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.
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.
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.
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.
肾缺血再灌注损伤（IRI）会使肾小球滤过率（GFR）急性下降，并在长期内损害肾功能。膜结合 Ha-Ras 抑制剂 Chaetomellic acid（KM）的预处理已证明对急性肾缺血具有有益作用。
我们测试了麦考酚酸酯（MMF，IRI 前 4 天每天 20mg），一种具有抗炎特性的免疫抑制剂，是否可以改善单侧肾切除大鼠 IRI 后的肾脏结局（肾缺血 45 分钟），单独或与 KM 联合使用。
缺血后 1 天，未治疗大鼠的 GFR 明显下降（与正常大鼠相比，-75%，P < 0.001），而 MMF 预处理并不能改变这种下降（-75%，P < 0.001 与正常相比）。KM（IRI 前 0.23μg/kg）极大地防止了 GFR 丧失（与正常相比，-39%，P < 0.05），但与 MMF 联合给药并没有进一步改善其作用（GFR，-45%，与正常相比，P < 0.05）。MMF 显著降低了 ICAM-1 表达和单核细胞募集（与未治疗大鼠相比，P < 0.05）；然而，MMF 大鼠的肾脏组织学与未治疗大鼠相似。另外一些大鼠在 IRI 后 6 个月进行了检查：IRI 后未治疗大鼠的肾功能下降（与正常相比，-42%，P < 0.01）和蛋白尿（与正常相比，P < 0.001）；MMF 预处理的大鼠表现出类似的模式，而 KM 预处理的大鼠的 GFR 更好（与正常相比，-20%，无显著差异），蛋白尿接近正常。KM + MMF 的联合治疗获得了相同的结果。
IRI 前用 MMF 预处理并不能为肾脏提供功能或形态保护，尽管一些炎症标志物的表达减少。MMF + KM 的联合治疗并没有为单独 KM 治疗提供额外的优势。
