Although up to 25% of glucose released into circulation in the postabsorptive state comes from renal gluconeogenesis, the regulatory mechanisms of this process are still poorly recognized, comparing to hepatic ones. The aim of the present study was to examine if hypoxia-inducible factor-1 (HIF-1) might be involved in the regulation of glucose de novo synthesis in kidneys. It was found that HK-2 cells (immortalized human kidney proximal tubules, capable of gluconeogenesis/glycogen synthesis) cultured with gluconeogenic substrates either in hypoxia (1% O2) or in the presence of DMOG (an inhibitor of HIF-1α degradation) exhibited increased glycogen content. This phenomenon was not correlated with augmented glucose intake and the effects were reversed by echinomycin (an inhibitor of HIF-1 binding to HRE sequence). As concluded from the measurement of the intracellular content of gluconeogenic intermediates followed by Western blot analysis, under conditions of hypoxia/increased HIF-1 level the activity of phosphoenolpyruvate carboxykinase (PEPCK) was elevated, as a result of increased expression of the cytosolic isoform of PEPCK (PEPCK-C). Chromatin immunoprecipitation (ChIP) analysis proved HIF-1 ability to bind to the promoter region of PEPCK-C gene. The final conclusion that hypoxia/HIF-1 accelerates the rate of renal glucogenesis via the mechanism engaging activation of PEPCK-C expression might be useful in terms of e.g. diabetes treatment, as it is commonly accepted that under diabetic conditions kidneys and liver seem to be equally important sources of glucose synthesized de novo.

中文翻译：

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缺氧可通过缺氧诱导性因子1依赖性磷酸烯醇丙酮酸羧化激酶表达的激活来增加肾脏糖原异生的速率。

尽管吸收后状态中高达25％的葡萄糖释放来自肾脏糖异生，但与肝脏相比，该过程的调节机制仍知之甚少。本研究的目的是检查缺氧诱导因子-1（HIF-1）是否可能参与肾脏葡萄糖从头合成的调节。发现在缺氧（1％O2）或存在DMOG（HIF-1α降解抑制剂）的条件下，用糖原异生底物培养的HK-2细胞（永生化的人肾近端肾小管，能够糖原异生/糖原合成）表现出糖原含量增加。这种现象与葡萄糖摄入量增加无关，而棘轮霉素（HIF-1抑制剂与HRE序列的结合）逆转了这种作用。从对糖异生中间体的细胞内含量进行测量并随后进行Western印迹分析得出的结论是，在缺氧/ HIF-1水平升高的情况下，由于烯醇式丙酮酸胞质同工型表达的增加，磷酸烯醇丙酮酸羧激酶（PEPCK）的活性也升高了。 PEPCK（PEPCK-C）。染色质免疫沉淀（ChIP）分析证明HIF-1能够结合PEPCK-C基因的启动子区域。缺氧/ HIF-1通过参与激活PEPCK-C表达的激活机制促进肾糖异生率的最终结论可能在例如糖尿病治疗方面有用，因为通常认为在糖尿病条件下，肾脏和肝脏似乎是从头合成的葡萄糖同样重要。