Peritubular capillary regression during the progression of experimental obstructive nephropathy
Peritubular capillary regression during the progression of experimental obstructive nephropathy
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DOI：
10.1097/01.asn.0000018408.51388.57
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发表时间：
2002-07-01
影响因子：
13.6
通讯作者：
Yamanaka, N
中科院分区：
文献类型：
--
作者：
Ohashi, R;Shimizu, A;Yamanaka, N
肾脏微血管损伤可能是导致肾脏疾病进展的一个主要因素。尽管小管周围毛细血管（PTC）的严重破坏可导致显着的小管间质瘢痕形成，但该过程的阐明仍不完整。本研究探讨了PTC在小管间质损伤过程中的形态学变化及其可能受到血管内皮生长因子（VEGF）的调控。采用左输尿管结扎法诱导Wistar大鼠单侧输尿管梗阻，择期取肾。免疫组织化学检测PTC lumina及VEGF及其受体Flk-1的表达。通过Ki67染色、末端脱氧核苷酸转移酶介导的dutp -生物素缺口末端标记和电子显微镜观察PTC内皮细胞的形态学变化。发病第1周，小管血管内皮生长因子免疫组化标记增强，伴有邻近血栓调节素（TM）阳性PTC管腔变形和扩张；Ki67和TM双染色显示内皮细胞有血管生成反应。在随后的2周内，管状VEGF标记减少，直到几乎不存在，Western blotting证实了这一效果。同时，PTC内皮细胞中VEGF受体Flk-1的标记减少，PTC lumina开始消退，表明内皮细胞凋亡（通过末端脱氧核苷酸转移酶介导的dutp -生物素缺口末端标记和电镜研究检测到）。到第4周结束时，在明显的管间质瘢痕区域，tm阳性PTC发光细胞的数量显著减少。这些结果表明，PTC回归，包括早期的、不持续的、血管生成反应，随后是进行性内皮细胞凋亡，可能是单侧输尿管梗阻模型中导致小管间质瘢痕形成的一个潜在因素。
Injury to the renal microvasculature may be a major factor contributing to the progression of renal disease. Although severe disruption of peritubular capillaries (PTC) could lead to marked tubulointerstitial scarring, elucidation of that process remains incomplete. This study investigated the morphologic changes in PTC and their likely regulation by vascular endothelial growth factor (VEGF) during the progression of tubulointerstitial injuries. Unilateral ureteral obstruction was induced in Wistar rats by ligation of the left ureter, and the kidneys were then collected at selected times. PTC lumina and the expression of VEGF and its receptor Flk-1 were immunohistochemically detected. Morphologic changes in PTC endothelial cells were examined by using Ki67 staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling, and electron-microscopic studies. In the first week of the disease period, immunohistochemical labeling of tubular VEGF intensified, with accompanying deformation and dilation of adjacent thrombomodulin (TM)-positive PTC lumina; an angiogenic response of endothelial cells was demonstrated with Ki67 and TM double-staining. During the subsequent 2 wk, tubular VEGF labeling decreased until it was virtually absent, an effect confirmed by Western blotting. Concomitantly, labeling of the VEGF receptor Flk-1 in PTC endothelial cells decreased and PTC lumina began to regress, demonstrating endothelial cell apoptosis (as detected in terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling and electron-microscopic studies). By the end of week 4, the numbers of TM-positive PTC lumina were significantly decreased in areas of marked tubulointerstitial scarring. These results suggest that PTC regression, involving an early, unsustained, angiogenic response followed by progressive endothelial cell apoptosis, could be a potential factor contributing to tubulointerstitial scarring in this unilateral ureteral obstruction model.