Reduced adenosine A2a receptor–mediated efferent arteriolar vasodilation contributes to diabetes-induced glomerular hyperfiltration

Abstract

Diabetes is associated with increased risk for development of kidney disease, and an increased glomerular filtration rate is an early indication of altered kidney function. Here we determine whether reduced adenosine A2a receptor-mediated vasodilation of the efferent arteriole contributes to the increased glomerular filtration rate in diabetes. The glomerular filtration rate, renal blood flow, and proximal tubular stop flow pressure were investigated in control and streptozotocin-diabetic rats during baseline and after administration of the adenosine A2a receptor antagonist ZM241385 or the adenosine A2a receptor agonist CGS21680. The diabetes-induced glomerular hyperfiltration was reduced by 24% following A2a receptor stimulation but was unaffected by A2a receptor inhibition. Contrarily, glomerular filtration rate in controls increased by 22% after A2a receptor inhibition and was unaffected by A2a stimulation. The increased glomerular filtration rate after A2a receptor inhibition in controls and decreased glomerular filtration rate after A2a receptor activation in diabetics were caused by increased and decreased stop flow pressure, respectively. None of the interventions affected renal blood flow. Thus, the normal adenosine A2a receptor-mediated tonic vasodilation of efferent arterioles is abolished in the diabetic kidney. This causes increased efferent arteriolar resistance resulting in increased filtration fraction and hyperfiltration.

Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease

“…Another subtype of adenosine receptor A2, involving A2aAR and A2bAR, mediates vasodilation at higher concentrations ( 76 ). Under normal circumstances, compared to A2bAR, A2aAR has a higher affinity for efferent arterioles and preferentially dilates the efferent arterioles, maintaining GFR in a normal range ( 85 , 86 ). Interestingly, in diabetes, the effect of adenosine A2aAR is diminished, increasing the resistance of efferent arterioles leading to the elevation of the filtration fraction and GFR ( 86 , 87 ).…”

Adenosine A2a receptor stimulation prevents proteinuria in diabetic rats by promoting an anti-inflammatory phenotype without affecting oxidative stress

“…, Persson et al . ). Besides its vasoactive properties, adenosine is an important regulator of tubular transport and immune system activity.…”

Erroneous data on renal hemodynamics derived from DCE‐MRI in rats

“…Thus, values for RBF in SD rats of comparable body weight and kidney weight are at least twice as high as reported by Wu et al and mostly in the range of 7-9 mL/min per g kw. [2][3][4] Even though the GFR data given by Wu et al are rather low as compared to those obtained by clearance techniques, 2-4 the filtration fraction (FF 5 GFR/effective renal plasma flow 5 GFR/RBF * (1 -hematocrit); reported hematocrit: 0.42 1 ) derived from their data would be about 62%. FF as determined by gold standard methods is 15-30% in SD rats.…”

“…FF as determined by gold standard methods is 15-30% in SD rats. [2][3][4] If FF were indeed 62%, then the hematocrit of the blood in efferent arterioles would amount to 0.65. At such an excessive hematocrit the viscosity of the blood increases to an extent that would jeopardize its flow.…”