Rosenberger Christian, Griethe Wanja, Gruber Gertrud, Wiesener Michael, Frei Ulrich, Bachmann Sebastian, Eckardt Kai-Uwe
Department of Nephrology and Medical Intensive Care, Charité, Humboldt University, Berlin, Germany.
Kidney Int. 2003 Sep;64(3):874-86. doi: 10.1046/j.1523-1755.2003.00159.x.
Hypoxia is believed to play an important role in the pathogenesis of acute and chronic kidney disease. However, the impact of low oxygen tensions on cellular functions in the kidney and potential adaptive responses are poorly understood.
In order to assess the effects of regional hypoxia, we induced large segmental renal infarcts in rats by renal artery branch ligation to create an oxygen gradient vertical to the corticomedullary axis and studied the effects on cell morphology, the induction of hypoxia-inducible transcription factors (HIF), the expression of HIF target genes, and cell proliferation.
Pimonidazol protein adduct immunohistochemistry, a marker for severe tissue hypoxia, verified a continuous area of hypoxic renal tissue extending from the cortex to the papilla, in which tubular necrosis developed subsequently. Within this area local sparing of pimonidazol staining and tissue preservation was found around arcuate veins, indicating regional oxygen supply via diffusion from venous blood. HIF-1alpha was up-regulated within 1 hour and for up to 7 days predominantly in the border zone of the infarct in tubular cells, glomerular cells, resident interstitial cells, capillary endothelial cells, and infiltrating macrophages. HIF-2alpha expression was less prominent and confined to resident and infiltrating peritubular cells in the cortex. HIF expression was colocalized with regional up-regulation of the hypoxia-inducible genes heme oxygenase-1 and vascular endothelial growth factor (VEGF), and was followed by capillary and tubular proliferation.
Our findings illustrate a marked potential of renal tissue to respond to regional ischemia and initiate adaptive reactions, including angiogenesis.
缺氧被认为在急性和慢性肾脏疾病的发病机制中起重要作用。然而，低氧张力对肾脏细胞功能的影响以及潜在的适应性反应尚不清楚。
为了评估局部缺氧的影响，我们通过结扎肾动脉分支在大鼠中诱导大片段肾梗死，以建立垂直于皮质髓质轴的氧梯度，并研究其对细胞形态、缺氧诱导转录因子（HIF）的诱导、HIF靶基因的表达以及细胞增殖的影响。
匹莫硝唑蛋白加合物免疫组化是严重组织缺氧的标志物，证实了从皮质延伸至乳头的连续缺氧肾组织区域，随后在该区域发生肾小管坏死。在该区域内，在弓形静脉周围发现了匹莫硝唑染色局部 sparing 和组织保存，表明通过静脉血扩散进行局部供氧。HIF-1α在1小时内上调，并在长达7天内主要在梗死边缘区的肾小管细胞、肾小球细胞、驻留间质细胞、毛细血管内皮细胞和浸润巨噬细胞中上调。HIF-2α表达不那么突出，局限于皮质中的驻留和浸润肾小管周细胞。HIF表达与缺氧诱导基因血红素加氧酶-1和血管内皮生长因子（VEGF）的区域上调共定位，随后是毛细血管和肾小管增殖。
我们的研究结果表明肾组织对局部缺血作出反应并启动适应性反应（包括血管生成）的显著潜力。
