Adenosine A2B Receptor-mediated VEGF Induction Promotes Diabetic Glomerulopathy

Angel Cárdenas; Camilo Toledo; Carlos Oyarzún; Angélica Sepúlveda; Claudia Quezada; Elena Guillén-Gómez; Montserrat M Díaz-Encarnación; Marçal Pastor-Anglada; Rody San Martín

Disclosures

Lab Invest. 2013;93(1):135-144. 

In This Article

Abstract and Introduction

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 A2B receptor (A2BAR) mediates VEGF overproduction in ex vivo glomeruli exposed to high glucose concentration, requiring PKCα and Erk1/2 activation. The glomerular content of A2BAR was concomitantly increased with VEGF at early stages of renal disease in streptozotocin-induced diabetic rats. Further, in vivo administration of an antagonist of A2BAR 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.

Introduction

Diabetes mellitus is a metabolic disease showing a dramatic increase of affected people worldwide.[1] Diabetic nephropathy (DN) is a diabetes-derived complication that continues to be the primary cause of terminal renal illness throughout the world,[2] affecting up to 30% of diabetic people. Patients with DN live with a high risk of developing cardiovascular disease and their quality of life worsens with progression of the disease. The economic and social impacts of the illness are high, as DN predisposes patients to undergo hemodialysis programs and possible renal transplant at advanced stages. Up to date, strict controls of glycemia and arterial blood pressure, as well as the use of the renin–angiotensin system blockers have been only modestly successful in retarding DN progression.[3,4] Thus, identification of new therapeutic alternatives remains to be a challenge for research in this field.

It has been shown at the onset of DN that podocytopathy and alterations of the filtration barrier occur, which clinically correspond to hyperfiltration and microalbuminuria. In addition, mesangial expansion with exacerbated extracellular matrix accumulation is a remarkable feature of this disease, which histologically appears as glomeruloesclerosis.[5] The disruption of the vascular endothelial growth factor (VEGF)/nitric oxide axis has been recognized as a key event leading to the progression of DN.[6] Further, overproduction of VEGF in transgenic animals is sufficient to resemble the glomerular alterations seen in DN.[7,8] Moreover, biopsies from type 1 and type 2 diabetic patients with early renal damage show an increased glomerular VEGF.[9–13] Therefore, identification of upstream mediators of VEGF overproduction is critical for identifying the pathogenesis of this disease.

Interestingly, early observations in the diabetic rat kidney showed that adenosine levels were significantly increased in the renal vein plasma compared with the renal artery.[14] It has been described that the equilibrative nucleoside transporters (ENTs), characterized by its sodium-independent facilitative transport activity, could have a major contribution on adenosine availability for signaling through adenosine receptor (AR).[15–21] ENTs activity mediates adenosine uptake to be either metabolized intracellularly, or to accumulate outside when the uptake activity is reduced. We have previously determined that the ENT1's activity decreased in diabetic rats' glomeruli[22] therefore, the handling of the nucleoside could be altered in this pathologic condition.

The cellular effects of adenosine are mediated by the P1 purinoceptor family enclosing A1, A2A, A2B and A3 AR subtypes.[23] Studies about the role of AR in the progression of DN in rats have attributed to the A2A subtype, a possible protective role in preventing inflammation-associated renal injury,[24] while a controversial role has been attributed to A1 subtype in mediating glomerular hyperfiltration.[25,26] We have determined that the nucleoside adenosine is a regulator of the VEGF production in glomeruli of rat in vitro.[27] Therefore, the correlation of adenosine levels and alterations of glomerular functions in the diabetic state, as well as the possible pharmacological intervention remain to be explored in vivo.

In this study, we show the role of adenosine A2B receptor (A2BAR) in mediating glomerular VEGF induction, which could be relevant in the pathological context because it correlates both the activity of a low-affinity receptor and the increased adenosine levels with the establishment of the diabetic glomerulopathy.

processing....