Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Abstract

Diabetic nephropathy ranks as the most devastating kidney disease worldwide. It characterizes in the early onset by glomerular hypertrophy, hyperfiltration and mesangial expansion. Experimental models show that overproduction of vascular endothelial growth factor (VEGF) is a pathogenic condition for podocytopathy; however the mechanisms that regulate this growth factor induction are not clearly identified. We determined that the adenosine A 2B receptor (A 2B AR) mediates VEGF overproduction in ex vivo glomeruli exposed to high glucose concentration, requiring PKCa and Erk1/2 activation. The glomerular content of A 2B AR was concomitantly increased with VEGF at early stages of renal disease in streptozotocin-induced diabetic rats. Further, in vivo administration of an antagonist of A 2B AR in diabetic rats blocked the glomerular overexpression of VEGF, mesangial cells activation and proteinuria. In addition, we also determined that the accumulation of extracellular adenosine occurs in glomeruli of diabetic rats. Correspondingly, raised urinary adenosine levels were found in diabetic rats. In conclusion, we evidenced that adenosine signaling at the onset of diabetic kidney disease is a pathogenic event that promotes VEGF induction.

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

“…61 The functional role of Adora2b signaling on VEGF release has been controversial, with some studies showing VEGF promotion and other studies showing VEGF reduction. 62,63 To our knowledge, the present studies provide the first genetic evidence for a functional role of Adora2b signaling in attenuating renal VEGF levels. Indeed, we found that renal VEGF expression was markedly increased in Adora2b gene-targeted mice after 16 weeks of diabetes compared with wild-type mice.…”

Adenosine A2Breceptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells

“…The association of adenosine and VEGF secretion dependent on A 2A or A 2B AR is also documented in multiple studies. 20,21 In this study, we found that A 2B rather than A 2A AR is implicated in the adenosine and NECA elicited upregulation of VEGF, based on the observation that an A 2A AR agonist CPA exerted a negligible effect on the expression of VEGF. In addition, A 2B has been observed to be preferentially expressed in human microvascular endothelial cells.…”

The effects of adenosine A2Breceptor inhibition on VEGF and nitric oxide axis-mediated renal function in diabetic nephropathy

“…Results obtained are comparable to the earlier in-vivo and in-vitro studies. 18,19 The differential expression of adenosine receptor was first described by Pawelczyk et al 20 The alteration turns off the inhibition on VEGF-A release accompanied by an increase in the production of this growth factor release in diabetic state.…”