Sun Dong, Feng Jiangmin, Dai Chun, Sun Li, Jin Tao, Ma Jianfei, Wang Lining
Department of Nephrology, First Affiliated Hospital of China Medical University, Shenyang City, Liaoning Province, PR China.
Am J Nephrol. 2006;26(4):363-71. doi: 10.1159/000094778. Epub 2006 Jul 26.
BACKGROUND/AIMS: To investigate the effects of peritubular capillary (PTC) loss and hypoxia on the progression of tubulointerstitial fibrosis in a rat model of aristolochic acid nephropathy (AAN).
Female Wistar rats received Caulis aristolochiae manshuriensis (CAM) decoction by gavage for 8 weeks, and were sacrificed at 8, 12 and 16 weeks, respectively, after administration. Blood urea nitrogen (BUN), serum creatinine (Scr) and urinary protein were monitored prior to sacrifice. PTC loss and tubulointerstitial hypoxia were assessed by CD34 immunostaining and hypoxia-inducible factor-alpha subunit 1 (HIF-1alpha) expression, respectively. Myofibroblasts were assessed by alpha-smooth muscle actin (alpha-SMA) expression. The expression of angiogenic factor was assessed by vascular endothelial growth factor (VEGF).
AAN rats differed from controls by increased BUN, Scr and 24-hour urinary protein excretion rates. There was a progressive loss of PTCs in the AAN model, which was associated with the decreased expression of VEGF. A significant increase in nuclear localization of HIF-1alpha was seen 16 weeks after treatment with CAM decoction in the context of severe tubulointerstitial damage. Multifocal tubulointerstitial fibrosis was seen in AAN rats at weeks 12 and 16, predominantly in the area of the outer stripe and outer medulla. No significant pathologic changes were found in control rats.
Following the reduction of PTCs density and up-regulation of HIF-1alpha, the tubulointerstitial fibrosis area increased. Ischemia and hypoxia are the important causes of severe tubulointerstitial fibrosis in AAN rats.
背景/目的：研究在马兜铃酸肾病（AAN）大鼠模型中，肾小管周围毛细血管（PTC）丢失及缺氧对肾小管间质纤维化进展的影响。
雌性Wistar大鼠经口灌胃给予关木通水煎剂8周，分别于给药后8周、12周和16周处死。处死前监测血尿素氮（BUN）、血清肌酐（Scr）和尿蛋白。分别通过CD34免疫染色和缺氧诱导因子α亚基1（HIF-1α）表达评估PTC丢失和肾小管间质缺氧。通过α平滑肌肌动蛋白（α-SMA）表达评估肌成纤维细胞。通过血管内皮生长因子（VEGF）评估血管生成因子的表达。
AAN大鼠的BUN、Scr和24小时尿蛋白排泄率高于对照组。AAN模型中PTC逐渐丢失，这与VEGF表达降低有关。在严重肾小管间质损伤的情况下，用关木通水煎剂治疗16周后，HIF-1α的核定位显著增加。在12周和16周时，AAN大鼠出现多灶性肾小管间质纤维化，主要位于外带和外髓质区域。对照组大鼠未发现明显病理变化。
随着PTC密度降低和HIF-1α上调，肾小管间质纤维化面积增加。缺血和缺氧是AAN大鼠严重肾小管间质纤维化的重要原因。
