Rosenberger Christian, Mandriota Stefano, Jürgensen Jan Steffen, Wiesener Michael S, Hörstrup Jan H, Frei Ulrich, Ratcliffe Peter J, Maxwell Patrick H, Bachmann Sebastian, Eckardt Kai-Uwe
Department of Nephrology and Medical Intensive Care, Charité, Campus Virchow-Klinikum, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
J Am Soc Nephrol. 2002 Jul;13(7):1721-32. doi: 10.1097/01.asn.0000017223.49823.2a.
Oxygen tensions in the kidney are heterogeneous, and their changes presumably play an important role in renal physiologic and pathophysiologic processes. A family of hypoxia-inducible transcription factors (HIF) have been identified as mediators of transcriptional responses to hypoxia, which include the regulation of erythropoietin, metabolic adaptation, vascular tone, and neoangiogenesis. In vitro, the oxygen-regulated subunits HIF-1alpha and -2alpha are expressed in inverse relationship to oxygen tensions in every cell line investigated to date. The characteristics and functional significance of the HIF response in vivo are largely unknown. High-amplification immunohistochemical analyses were used to study the expression of HIF-1alpha and -2alpha in kidneys of rats exposed to systemic hypoxia bleeding anemia, functional anemia (0.1% carbon monoxide), renal ischemia, or cobaltous chloride (which is known to mimic hypoxia). These treatments led to marked nuclear accumulation of HIF-1alpha and -2alpha in different renal cell populations. HIF-1alpha was mainly induced in tubular cells, including proximal segments with exposure to anemia/carbon monoxide, in distal segments with cobaltous chloride treatment, and in connecting tubules and collecting ducts with all stimuli. Staining for HIF-1alpha colocalized with inducible expression of the target genes heme oxygenase-1 and glucose transporter-1. HIF-2alpha was not expressed in tubular cells but was expressed in endothelial cells of a small subset of glomeruli and in peritubular endothelial cells and fibroblasts. The kidney demonstrates a marked potential for upregulation of HIF, but accumulation of HIF-1alpha and HIF-2alpha is selective with respect to cell type, kidney zone, and experimental conditions, with the expression patterns partly matching known oxygen profiles. The expression of HIF-2alpha in peritubular fibroblasts suggests a role in erythropoietin regulation.
肾脏中的氧张力是不均匀的，其变化可能在肾脏生理和病理生理过程中发挥重要作用。一类缺氧诱导转录因子（HIF）已被确定为对缺氧的转录反应的介质，其中包括对促红细胞生成素的调节、代谢适应、血管张力和新血管生成。在体外，迄今为止研究的每个细胞系中，氧调节亚基HIF-1α和-2α的表达与氧张力呈反比关系。HIF在体内反应的特征和功能意义在很大程度上尚不清楚。采用高放大倍数免疫组织化学分析方法，研究了暴露于全身性缺氧性出血性贫血、功能性贫血（0.1%一氧化碳）、肾缺血或氯化钴（已知可模拟缺氧）的大鼠肾脏中HIF-1α和-2α的表达。这些处理导致不同肾细胞群体中HIF-1α和-2α明显的核内积聚。HIF-1α主要在肾小管细胞中诱导表达，包括暴露于贫血/一氧化碳时的近端节段、氯化钴处理时的远端节段以及所有刺激下的连接小管和集合管。HIF-1α染色与靶基因血红素加氧酶-1和葡萄糖转运蛋白-1的诱导表达共定位。HIF-2α在肾小管细胞中不表达，但在一小部分肾小球的内皮细胞、肾小管周围内皮细胞和成纤维细胞中表达。肾脏显示出HIF上调的显著潜力，但HIF-1α和HIF-2α的积聚在细胞类型、肾区和实验条件方面具有选择性，其表达模式部分与已知的氧分布情况相符。肾小管周围成纤维细胞中HIF-2α的表达提示其在促红细胞生成素调节中发挥作用。
