慢性马兜铃酸肾病血小板反应因子1高表达与肾间质纤维化及微血管丢失的关系

目的 探讨血小板反应因子1（TSP-1）与慢性马兜铃酸肾病（CAAN）肾间质纤维化及肾小管周围毛细血管（PTC）丢失的关系。方法 36只SD大鼠被随机分为CAAN模型组（用关木通浸膏水溶液间断灌胃）及对照组（仅自来水灌胃），每组18只。分别于第4、8和12周处死6只大鼠，用肾组织切片做免疫组化染色。对TSP-1、转化生长因子-β1（TGF-β1）、氨基肽酶P（APP）、血管内皮生长因子（VEGF）及Ⅰ型胶原（ColⅠ）的表达进行半定量分析。结果 与对照组比较，模型组大鼠肾间质TSP-1、肾小管TGF-β1及肾间质Col Ⅰ表达均显著上调（P均〈0．01）。3者间表达量呈显著正相关（r=0．925、0．910、0．857，P均〈0．01）。模型组大鼠肾间质APP表达明显下调（P〈0．01），与TSP-1、Col Ⅰ表达量呈显著负相关（r=-0．945、-0．883，P均〈0．01）。模型组肾小管VEGF表达上调（P〈0．01），其表达量与APP呈显著负相关（r=-0．607，P〈0．01），而与TGF-β1星显著正相关（r=0．625，P〈0．01）。结论 TSP-1-TGF-β轴表达增强及与TSP-1相关的PTC丢失均可能参与CAAN肾间质纤维化，而VEGF表达上调为代偿表现。

Relationship of up-regulated thrombospondin 1 expression with renal interstitial fibrosis and peritubular capillary loss in chronic aristolochic acid nephropathy

Objective To investigate the relationship of up-regulated thrombospondin 1 (TSP-1) expression with renal interstitial fibrosis and peritubular capillary loss in chronic aristolochic acid nephropathy(CAAN). Methods Thirty-six male SD rats were randomly divided into two groups， 18 in each one. CAAN rats received 20 mg?kg-1?d-1 aristolochic acid (AA) contained in ethanol extract of Aristolochia manshuriensis Kom by gavage for 5 days in the 1st week， and after a break of 9 days， then 15 mg?kg-1?d-1 AA for 7 days in every other week up to the 12th week. Control group rats (Con) only received tap water by gavage as above. At the end of the 4th， 8th and 12th week， 6 rats in each group were sacrificed. Immunohistochemical staining was performed in rat renal tissue sections to examine the expression of TSP-1， transforming growth factor-β1 (TGF-β1)， aminopeptidase P(APP)， vascular endothelial growth factor (VEGF) and typeⅠcollagen (ColⅠ). Results Compared with Con， the expression levels of interstitial TSP-1， tubular TGF-β1 and interstitial ColⅠwere all up-regulated in CAAN rats (all P < 0.01)， meanwhile significantly positive correlations were found among them (TSP-1 vs TGF-β， r=0.925； TSP-1 vs ColⅠ，r=0.910； TGF-β1 vs ColⅠ r=0.857；all P < 0.01). Compared with Con， interstitial APP expression was significantly down-regulated in CAAN rats(P < 0.01)and correlated with interstitial TSP-1 and Col I expression(r=-0.945、-0.883，all P < 0.01)significantly and negatively. Compared with Con， tubular VEGF expression was significantly up-regulated in CAAN rats (P < 0.05 or < 0.01) and significantly correlated with TGF-β1(r=0.625， P < 0.01)and APP(r=-0.607， P < 0.01). Conclusions The up-regulated expression of TSP-1-TGF-β axis and the loss of peritubular capillaries related with TSP-1 may participate in the development of renal interstitial fibrosis in CAAN. The increased VEGF expression is probably a compensation phenomena.