HIF-1α expression follows microvascular loss in advanced murine adriamycin nephrosis
HIF-1α expression follows microvascular loss in advanced murine adriamycin nephrosis
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DOI：
10.1152/ajprenal.00244.2003
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发表时间：
2005-01-01
影响因子：
4.2
通讯作者：
Harris, DCH
中科院分区：
文献类型：
--
作者：
Kairaitis, LK;Wang, YP;Harris, DCH
细胞缺氧被认为是慢性肾损伤发病机制的一个主要因素，但迄今为止还没有直接证据支持其重要性。因此，我们在慢性肾损伤动物模型（小鼠阿霉素肾病；an）中，通过评估阿霉素给药后7,14和28天动物缺氧诱导因子-1 （hif -1 α）的氧依赖α亚基的核定位，研究了皮质缺氧。结合皮质微血管定量（CD34免疫染色）和皮质VEGF表达对结果进行评估。用末端脱氧核苷酸转移酶dUTP镍端标记染色检测皮质细胞凋亡。在严重肾小球和小管间质损伤的情况下，阿霉素治疗28天后，hif -1 α的核定位显著增加。核hif -1 α染色区域不与细胞凋亡区域共定位。AN也与小管周围毛细血管的明显衰减有关，在阿霉素使用后14天和28天尤为明显。阿霉素给药后第7天至第28天，皮质VEGF表达逐渐下降。总之，这些数据与小鼠AN晚期细胞缺氧的显著增加是一致的。皮质缺氧增加之前，小管周围毛细血管数量（即供氧）和血管生成细胞因子VEGF均显著减少。除了提供慢性肾脏疾病模型中细胞缺氧的第一个直接证据外，这些结果表明血管生成的原发性失调可能是该模型中缺氧增加的原因。
Cellular hypoxia has been proposed as a major factor in the pathogenesis of chronic renal injury, yet to date there has been no direct evidence to support its importance. Therefore, we examined cortical hypoxia in an animal model of chronic renal injury ( murine adriamycin nephrosis; AN) by assessing nuclear localization of the oxygen-dependent alpha-subunit of hypoxia-inducible factor-1 (HIF-1alpha) in animals 7, 14, and 28 days after adriamycin. Results were assessed in conjunction with quantitation of the cortical microvasculature (by CD34 immunostaining) and cortical expression of VEGF. Cortical apoptosis was also examined by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. A dramatic and significant increase in nuclear localization of HIF-1alpha was seen 28 days after adriamycin in the context of severe glomerular and tubulointerstitial damage. Areas of nuclear HIF-1alpha staining did not colocalize with areas of cellular apoptosis. AN was also associated with a significant attenuation of the peritubular capillaries that was significant at 14 and 28 days after adriamycin. Cortical VEGF expression fell in a stepwise manner from day 7 until day 28 after adriamycin. In conclusion, these data are consistent with a significant increase in cellular hypoxia occurring in the advanced stages of murine AN. Increased cortical hypoxia was preceded by significant reductions in both the number of peritubular capillaries (i.e., oxygen supply) and the angiogenic cytokine VEGF. Apart from providing the first direct evidence for cellular hypoxia in a model of chronic renal disease, these results suggest that a primary dysregulation of angiogenesis may be the cause of increased hypoxia in this model.