The impact of artificial sweeteners on VEGF-induced permeability in glomerular microvascular endothelium

Increasing economic and personal cost of diabetic kidney disease (DKD) globally, highlights the importance of developing alternative treatment strategies for the disease, since there are very limited treatment approaches. Characterised by increase in urinary albumin excretion and decrease in glomerular filtrate rate, individuals suffering from DKD at an advanced stage require kidney dialysis and organ transplantation. To manage DKD, maintaining close to normal blood glucose level is a prerequisite which has led to a shift towards the use of alternative sugar substitutes such as artificial sweeteners. Although considered safe by Food Standards Agency and well tolerated, the impact of artificial sweeteners in circulation and on vascular permeability associated with DKD is lacking. The discovery of sweet taste receptors in extraoral cells has led to questions on their physiological roles besides sweet taste satiation. This research, therefore, employed various experimental approach to better comprehend the effects of artificial sweeteners, aspartame, neotame, saccharin and sucralose on VEGF-induced permeability through activation of sweet taste-dependent signalling pathways. To mimic endothelial permeability associated with DKD in vitro, glomerular microvascular endothelial cells were exposed to VEGF with and without artificial sweeteners, using FITC-dextran as a tracer to evaluate the amount of leak across the cell monolayer. An analytical technique, gas chromatography-mass spectrometry (GC-MS) was utilised to validate the binding of the sweetener to its receptor. Findings demonstrated novel protective effects of saccharin and sucralose on VEGF-induced permeability through activation of the sweet taste receptor, T1R3, and maintenance of the cell-cell junctional protein, VE-cadherin. GC-MS results showed that sucralose was unable to cross the cell membrane of glomerular microvasculature. Whilst controversy remains regarding consumption of AS, these novel findings, that some artificial sweeteners attenuate VEGF-induced vascular permeability, may represent an alternate treatment strategy towards ameliorating vascular permeability and improving renal function in individuals living with DKD.