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  • Title: Hypoxia increases the rate of renal gluconeogenesis via hypoxia-inducible factor-1-dependent activation of phosphoenolpyruvate carboxykinase expression.
    Author: Owczarek A, Gieczewska K, Jarzyna R, Jagielski AK, Kiersztan A, Gruza A, Winiarska K.
    Journal: Biochimie; 2020; 171-172():31-37. PubMed ID: 32045650.
    Abstract:
    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.
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