Abstract
As glucose is a mandatory nutrient for cell proliferation and renewal, it is suspected that glucose microenvironment is sensed by all cell types to regulate angiogenesis. Several glucose‐sensing components have been partially described to respond to high glucose levels. However, little is known about the response to low glucose. Here, we used well‐differentiated isolated normal rat renal tubules under normal oxygenation conditions to assess the angiogenic response to low glucose. In apparent paradox, but confirming observations made separately in other models, high glucose but also low glucose increased mRNA level of vascular endothelial growth factor A (VEGFA). A subset of mRNAs including hypoxia‐inducible factor 1A (HIF1A), angiopoietin receptor (TIE‐2), and VEGF receptor 2 (FLK1) were similarly glucose‐sensitive and responded to low glucose by increased stability independently of HIF1A and HIF2A proteins. These results contribute to gain some insights as to how normal cells response to low glucose may play a role in the tumor microenvironment.
Highlights
Glucose is a mandatory nutrient for cell proliferation and renewal (Locasale and Cantley 2011)
The results showed that low glucose in the microenvironment of normal kidney cells increases a series of mRNAs involved in angiogenesis including vascular endothelial growth factorA (VEGFA), hypoxia-inducible factor 1A (HIF1A), and HIF2A themselves
Low glucose increases VEGFA mRNA and a subset of mRNAs involved in angiogenesis and glucose consumption
Summary
Glucose is a mandatory nutrient for cell proliferation and renewal (Locasale and Cantley 2011). It is recognized that VEGF receptors, believed so far to be restricted to endothelial cells, are expressed widely (Koch and Claesson-Welsh 2012) Their regulator HIF contains two subunits, HIFA and HIFB, the former being sensitive to oxygen pressure that controls both its protein stability and transcriptional activity. Studies in tumor cells showed that HIF1A and HIF2A mRNA levels are not regulated by oxygen (Maxwell et al 1999; Heidbreder et al 2003) It is not known whether they are sensitive to other nutrients. The results showed that low glucose in the microenvironment of normal kidney cells increases a series of mRNAs involved in angiogenesis including VEGFA, HIF1A, and HIF2A themselves. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society
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