Bloudícková S, Rajnoch J, Lodererová A, Honsová E, Viklický O
Department of Nephrology, Transplant Center, Prague, Czech Republic.
Kidney Blood Press Res. 2006;29(1):60-6. doi: 10.1159/000092948. Epub 2006 Apr 26.
Renal ischemia and hypertension have been suggested to be involved in the progression of renal diseases. Recently, we developed a model of accelerated major histocompatibility complex-independent renal injury, where high-renin hypertension aggravates functional and morphological changes induced by ischemia/reperfusion (I/R). In this model, we evaluated the effect of immunosuppressant mycophenolate mofetil (MMF) to test its capability to slow the progression of accelerated nephropathy.
34 anesthetized uninephrectomized hypertensive transgenic (mREN2)27 rats (TGR) received a clamp on the renal pedicle for 45 min. Animals were treated with MMF 10 mg/kg/day (n = 10), 20 mg/kg/day (n = 10) or placebo (n = 10) orally via gavage for 12 weeks. Four animals were sham operated and not treated. Proteinuria and blood pressure were evaluated throughout the experiment. At the end of the experiment, kidney function was evaluated and kidneys harvested for morphological analysis and immunohistochemistry (CD4+, CD8+ lymphocytes and specific rat monocyte/macrophage marker ED-1+ cells).
At week 12, both MMF-treated groups had lower proteinuria as compared to the placebo group (MMF 10: 22.4 +/- 9.8, MMF 20: 20.9 +/- 5.6 vs. 126.7 +/- 35.8; p < 0.01; sham 28.1 +/- 1.4 mg/day) and reduced glomerulosclerosis (MMF 10: 11.4 +/- 7.8, MMF 20: 5.2 +/- 2.7 vs. 20.9 +/- 10.9; p < 0.05; sham 15.7 +/- 9.2%). There were no differences in systolic blood pressure among groups. MMF-treated rats had lower CD4+ (MMF 10: 61.2 +/- 46.4, MMF 20: 29.3 +/- 18.2 vs. 125.3 +/- 42.8; p < 0.01, sham 84.9 +/- 6.1 cells/field of view) and CD8+ (MMF 10: 13.7 +/- 10.2, MMF 20: 10.0 +/- 8.1 vs. 37.8 +/- 14.3; p < 0.01; sham: 31.8 +/- 7.6 cells/field of view) lymphocytes infiltration and ED-1 macrophages infiltration (MMF 10: 5.5 +/- 6.4, MMF 20: 2.5 +/- 2.8 vs. 16.7 +/- 4.1; p < 0.01; sham 12.2 +/- 4.6 cells/field of view) than placebo-treated rats.
Our results thus support the hypothesis about the key role of immune mechanisms in progression of chronic nephropathies.
肾缺血和高血压被认为与肾脏疾病的进展有关。最近，我们建立了一种加速的主要组织相容性复合体非依赖性肾损伤模型，其中高肾素性高血压会加重缺血/再灌注（I/R）诱导的功能和形态学变化。在该模型中，我们评估了免疫抑制剂霉酚酸酯（MMF）的效果，以测试其减缓加速性肾病进展的能力。
34只麻醉状态下的单肾切除高血压转基因（mREN2）27大鼠（TGR），肾蒂夹闭45分钟。动物通过灌胃口服给予MMF 10毫克/千克/天（n = 10）、20毫克/千克/天（n = 10）或安慰剂（n = 10），持续12周。4只动物进行假手术且未接受治疗。在整个实验过程中评估蛋白尿和血压。实验结束时，评估肾功能，并摘取肾脏进行形态学分析和免疫组织化学检测（CD4 +、CD8 +淋巴细胞以及特异性大鼠单核细胞/巨噬细胞标志物ED-1 +细胞）。
在第12周时，与安慰剂组相比，两个MMF治疗组的蛋白尿水平均较低（MMF 10：22.4±9.8，MMF 20：20.9±5.6 vs. 126.7±35.8；p < 0.01；假手术组28.1±1.4毫克/天），肾小球硬化程度降低（MMF 10：11.4±7.8，MMF 20：5.2±2.7 vs. 20.9±10.9；p < 0.05；假手术组15.7±9.2%）。各组间收缩压无差异。与安慰剂治疗的大鼠相比，MMF治疗的大鼠CD4 +（MMF 10：61.2±46.4，MMF 20：29.3±18.2 vs. 125.3±42.8；p < 0.01，假手术组84.9±6.1个细胞/视野）和CD8 +（MMF 10：13.7±10.2，MMF 20：10.0±8.1 vs. 37.8±14.3；p < 0.01；假手术组：31.8±7.6个细胞/视野）淋巴细胞浸润以及ED-1巨噬细胞浸润（MMF 10：5.5±6.4，MMF 20：2.5±2.8 vs. 16.7±4.1；p < 0.01；假手术组为12.2±4.6个细胞/视野）均较少。
因此，我们的结果支持了免疫机制在慢性肾病进展中起关键作用这一假说。
