Adenosine A(2B) receptor-mediated VEGF induction promotes diabetic glomerulopathy.
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 PKCα 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.
Laboratorio de Patología Molecular, Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
Angel
A
Cárdenas
Camilo
C
Toledo
Carlos
C
Oyarzún
Angélica
A
Sepúlveda
Claudia
C
Quezada
Elena
E
Guillén-Gómez
Montserrat M
MM
Díaz-Encarnación
Marçal
M
Pastor-Anglada
Rody
R
San Martín
D000081:Acetamides / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism / Q000652:urine; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000652:urine; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000652:urine; D006651:Histocytochemistry; D007678:Kidney Glomerulus / Q000737:chemistry / Q000378:metabolism; D008297:Male; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D000081:Acetamides; D001786:Blood Glucose; C423842:N-(4-cyanophenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy)acetamide; D011687:Purines; D043704:Receptor, Adenosine A2B; D042461:Vascular Endothelial Growth Factor A; D000241:Adenosine