Angiotensin II contributes to glomerular hyperfiltration in diabetic rats independently of adenosine type I receptors

Abstract

Increased angiotensin II (ANG II) or adenosine can potentiate each other in the regulation of renal hemodynamics and tubular function. Diabetes is characterized by hyperfiltration, yet the roles of ANG II and adenosine receptors for controlling baseline renal blood flow (RBF) or tubular Na(+) handling in diabetes is presently unknown. Accordingly, the changes in their functions were investigated in control and 2-wk streptozotocin-diabetic rats after intrarenal infusion of the ANG II AT1 receptor antagonist candesartan, the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or their combination. Compared with controls, the baseline blood pressure, RBF, and renal vascular resistance (RVR) were similar in diabetics, whereas the glomerular filtration rate (GFR) and filtration fraction (FF) were increased. Candesartan, DPCPX, or the combination increased RBF and decreased RVR similarly in all groups. In controls, the GFR was increased by DPCPX, but in diabetics, it was decreased by candesartan. The FF was decreased by candesartan and DPCPX, independently. DPCPX caused the most pronounced increase in fractional Na(+) excretion in both controls and diabetics, whereas candesartan or the combination only affected fractional Li(+) excretion in diabetics. These results suggest that RBF, via a unifying mechanism, and tubular function are under strict tonic control of both ANG II and adenosine in both control and diabetic kidneys. Furthermore, increased vascular AT1 receptor activity is a contribution to diabetes-induced hyperfiltration independent of any effect of adenosine A1 receptors.

Fig. 1.

Outline of the two protocols. A: protocol used for determining the dose-response curve for the angiotensin II (ANG II) AT₁ receptor antagonist candesartan, or the adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or the combination of the two. B: protocol used for investigating the roles of AT₁ and A₁ receptors on the regulation of intrarenal hemodynamics and tubular Na⁺ handling. STZ, streptozotocin.

Fig. 2.

Dose-response curves for the AT₁ receptor antagonist candesartan (A), the A₁ receptor antagonist DPCPX (B), or the combination of the two (C) on mean arterial pressure, total renal blood flow and renal vascular resistance. Results expressed as means ± SE for n = 5–9/group. *P < 0.05 vs. time 0.

Fig. 3.

Vascular effects of the in vivo intrarenal blockade of ANG II and adenosine receptors. Mean arterial pressure, total renal blood flow, renal vascular resistance, glomerular filtration rate, and filtration fraction of control and diabetic animals before and after blockade of AT₁ receptors by candesartan (4.2 μg/kg), A₁ receptors by DPCPX (140 μg/kg), or the combined blockade of AT₁ and A₁ receptors. Results expressed as means ± SE for n = 8–16. *P < 0.05 vs. baseline within the same group. #P < 0.05 vs. corresponding control.

Fig. 4.

Tubular effects of the in vivo intrarenal blockade of ANG II and adenosine receptors. Urine flow, fractional urinary Na⁺ excretion, fractional urinary Li⁺ excretion, transported Na⁺ and total kidney oxygen consumption of control and diabetic animals before and after blockade of AT₁ receptors by candesartan (4.2 μg/kg), A₁ receptors by DPCPX (140 μg/kg), or the combined blockade of AT₁ and A₁ receptors. Results expressed as means ± SE for n = 8–16. *P < 0.05 vs. baseline within the same group. #P < 0.05 vs. corresponding control.