Kim Won
Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea.
Electrolyte Blood Press. 2008 Jun;6(1):22-6. doi: 10.5049/EBP.2008.6.1.22. Epub 2008 Jun 30.
Injury to the renal microvasculature and inflammatory process may be major factors in the progression of renal disease, therefore, protection of the renal endothelial cell and regulation of inflammatory process may be an important therapeutic target of renal disease. Thus, we evaluated the protective effect of cartilage oligomeric matrix protein-angiopoietin-1 (COMP-Ang1) in unilateral ureteral obstruction (UUO)-induced renal fibrosis, cyclosporine A (CsA)-induced renal injury, and the diabetic nephropathy model. In the UUO model, morphologic examination indicated less tubular injury and tubulointerstitial fibrosis in mice that received COMP-Ang1 compared to vehicle-treated mice. Interstitial type I collagen, myofibroblast accumulation, renal surface microvasculature and renal blood flow were higher after treatment with COMP-Ang1 compared to vehicle-treated mice. COMP-Ang1 treatment decreased monocyte/macrophage infiltration, tissue levels of transforming growth factor β1, and Smad 2/3 phosphorylation and increased Smad 7 in the obstructed kidney. In CsA-induced renal injury, histologic examination showed significantly decreased CsA-induced tubular damage and tubulointerstitial fibrosis in COMP-Ang1 treated mice. COMP-Ang1 administration also decreased increased macrophage infiltration, adhesion molecule expression, TGF-β1, and Smad 2/3 levels in CsA-treated kidneys, while increasing Smad 7 levels. Laser-Doppler sonographic findings and endothelial factor VIII staining revealed that COMP-Ang1 had a preservative effect on peritubular vasculature. In the diabetic nephropathy model, COMP-Ang1 reduced albuminuria and decreased mesangial expansion, thickening of the glomerular basement membrane and podocyte foot process broadening and effacement. COMP-Ang1 may delay the fibrotic changes in the kidney of diabetic db/db mice through its anti-inflammatory or metabolic effects. In conclusion, COMP-Ang1 may be an endothelium-specific and anti-inflammatory therapeutic modality in fibrotic renal disease.
肾微血管损伤和炎症过程可能是肾脏疾病进展的主要因素，因此，保护肾内皮细胞和调节炎症过程可能是肾脏疾病的一个重要治疗靶点。因此，我们评估了软骨寡聚基质蛋白-血管生成素-1（COMP-Ang1）在单侧输尿管梗阻（UUO）诱导的肾纤维化、环孢素A（CsA）诱导的肾损伤及糖尿病肾病模型中的保护作用。在UUO模型中，形态学检查表明，与接受载体处理的小鼠相比，接受COMP-Ang1的小鼠肾小管损伤和肾小管间质纤维化较轻。与载体处理的小鼠相比，COMP-Ang1处理后间质I型胶原、肌成纤维细胞积聚、肾表面微血管和肾血流量更高。COMP-Ang1处理可减少单核细胞/巨噬细胞浸润、转化生长因子β1的组织水平以及Smad 2/3磷酸化，并增加梗阻肾脏中Smad 7的表达。在CsA诱导的肾损伤中，组织学检查显示，COMP-Ang1处理的小鼠中CsA诱导的肾小管损伤和肾小管间质纤维化明显减轻。给予COMP-Ang1还可减少CsA处理的肾脏中巨噬细胞浸润增加、黏附分子表达、TGF-β1和Smad 2/3水平，同时增加Smad 7水平。激光多普勒超声检查结果和内皮因子VIII染色显示，COMP-Ang1对肾小管周围血管有保护作用。在糖尿病肾病模型中，COMP-Ang1减少蛋白尿，并减少系膜扩张、肾小球基底膜增厚以及足细胞足突增宽和消失。COMP-Ang1可能通过其抗炎或代谢作用延缓糖尿病db/db小鼠肾脏的纤维化改变。总之，COMP-Ang1可能是纤维化肾脏疾病中一种内皮细胞特异性的抗炎治疗方式。
