Kim Won, Moon Sang-Ok, Lee Sang Yong, Jang Kyu Yun, Cho Chung-Hyun, Koh Gou Young, Choi Kyu-Sil, Yoon Kwon-Ha, Sung Mi Jeong, Kim Duk Hoon, Lee Sik, Kang Kyung Pyo, Park Sung Kwang
Renal Regeneration Laboratory and Department of Internal Medicine, Chonbuk National University Medical School, San 2-20 Keumam-dong, Jeonju, 561-180, South Korea.
J Am Soc Nephrol. 2006 Sep;17(9):2474-83. doi: 10.1681/ASN.2006020109. Epub 2006 Aug 2.
Injury to the renal microvasculature may be a major factor in the progression of renal disease; therefore, protection of endothelial cells (EC) in renal vasculature may have a therapeutic role in renal fibrosis. Recently, a soluble, stable, and potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1, was developed. The contribution of COMP-Ang1 in renal interstitial fibrosis, however, remains to be clarified. This study investigated the effects of COMP-Ang1 on peritubular capillary EC in the renal cortex and the renal fibrogenic process that is triggered by unilateral ureteral obstruction. COMP-Ang1 preserved renal platelet-EC adhesion molecule-1-and Tie2-positive EC. Morphologic examination indicated less tubular injury and tubulointerstitial fibrosis in mice that received COMP-Ang1 than vehicle-treated mice. Interstitial type I collagen and myofibroblast accumulation were significantly suppressed by COMP-Ang1 treatment. COMP-Ang1 increased Tie2 and Akt phosphorylation in ureteral obstructed kidneys. Renal surface microvasculature and renal blood flow were higher after treatment with COMP-Ang1 than with vehicle. COMP-Ang1 treatment decreased monocyte/macrophage infiltration, tissue levels of TGF-beta1, and Smad 2/3 phosphorylation and increased Smad 7 in the obstructed kidney. These results demonstrate that COMP-Ang1 treatment can decrease the progression of renal fibrosis in unilateral ureteral obstruction. COMP-Ang1 may be an endothelium-specific therapeutic modality in fibrotic renal disease.
肾微血管损伤可能是肾病进展的一个主要因素；因此，保护肾血管中的内皮细胞（EC）可能在肾纤维化中具有治疗作用。最近，一种可溶性、稳定且有效的血管生成素-1（Ang1）变体，即软骨寡聚基质蛋白（COMP）-Ang1被研发出来。然而，COMP-Ang1在肾间质纤维化中的作用仍有待阐明。本研究调查了COMP-Ang1对肾皮质肾小管周围毛细血管EC以及单侧输尿管梗阻引发的肾纤维化过程的影响。COMP-Ang1可保护肾血小板-EC黏附分子-1和Tie2阳性的EC。形态学检查表明，接受COMP-Ang1治疗的小鼠肾小管损伤和肾小管间质纤维化程度低于接受载体治疗的小鼠。COMP-Ang1治疗可显著抑制间质I型胶原蛋白和肌成纤维细胞的积聚。COMP-Ang1可增加输尿管梗阻肾脏中Tie2和Akt的磷酸化。COMP-Ang1治疗后肾表面微血管和肾血流量高于载体治疗。COMP-Ang1治疗可减少单核细胞/巨噬细胞浸润、TGF-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。这些结果表明，COMP-Ang1治疗可减轻单侧输尿管梗阻肾纤维化的进展。COMP-Ang1可能是纤维化肾病中一种内皮细胞特异性的治疗方式。
