Deficient
insulin signaling is a key event mediating diabetic glomerulopathy. Additionally,
diabetic kidney disease has been related to increased levels of
adenosine. Therefore, we tested a link between
insulin deficiency and dysregulated activity of the equilibrative
nucleoside transporters (ENTs) responsible for controlling extracellular levels of
adenosine. In ex vivo glomeruli, high
D-glucose decreased
nucleoside uptake mediated by ENT1 and ENT2 transporters, resulting in augmented extracellular levels of
adenosine. This condition was reversed by exposure to
insulin. Particularly,
insulin through
insulin receptor/PI3K pathway markedly upregulated ENT2 uptake activity to restores the extracellular basal level of
adenosine. Using primary cultured rat podocytes as a cellular model, we found
insulin was able to increase ENT2 maximal velocity of transport. Also, PI3K activity was necessary to maintain ENT2
protein levels in the long term. In glomeruli of
streptozotocin-induced diabetic rats,
insulin deficiency leads to decreased activity of ENT2 and chronically increased extracellular levels of
adenosine. Treatment of diabetic rats with
adenosine deaminase attenuated both the glomerular loss of
nephrin and
proteinuria. In conclusion, we evidenced ENT2 as a target of
insulin signaling and sensitive to dysregulation in diabetes, leading to chronically increased extracellular
adenosine levels and thereby setting conditions conducive to kidney injury.