Reduced adenosine A2a receptor–mediated efferent arteriolar vasodilation contributes to diabetes-induced glomerular hyperfiltration  Patrik Persson, Peter Hansell, Fredrik Palm  Kidney International  Volume 87, Issue 1, Pages 109-115 (January 2015) DOI: 10.1038/ki.2014.219 Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 1 Adenosine A2a receptor control of glomerular filtration rate is absent in diabetic rats, i.e., glomerular filtration rate is regulated by addition of an A2a receptor agonist but not by an antagonist. Glomerular filtration rate in control and diabetic rats during baseline (BL) and after treatment with either the adenosine A2a antagonist ZM241385 (a) or the adenosine A2a agonist CGS21680 (b). *P<0.05 compared with baseline in controls and #P<0.05 compared with baseline in diabetics analyzed by Bonferroni’s multiple comparisons test. Result from two-way analysis of variance: (a) interaction: not significant, diabetes: P<0.05, ZM241385: P<0.05. (b) Interaction: P<0.05, diabetes: P<0.05, CGS21680: P<0.05. Kidney International 2015 87, 109-115DOI: (10.1038/ki.2014.219) Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 2 Adenosine A2a receptors do not control renal blood flow. Renal blood flow in control and diabetic rats during baseline (BL) and after treatment with either the adenosine A2a antagonist ZM241385 (a) or the adenosine A2a agonist CGS21680 (b). Compared with baseline in controls and #P<0.05 compared with baseline in diabetics analyzed by Bonferroni’s multiple comparisons test. Result from two-way analysis of variance: (a) interaction: not significant (NS), diabetes: P<0.05, ZM241385: NS. (b) Interaction: P<0.05, diabetes: NS, CGS21680: NS. Kidney International 2015 87, 109-115DOI: (10.1038/ki.2014.219) Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 3 Filtration fraction is regulated by adenosine A2a receptors in controls but this regulation is absent in diabetes. Filtration fraction in control and diabetic rats during baseline (BL) and after treatment with either the adenosine A2a antagonist ZM241385 (a) or the adenosine A2a agonist CGS21680 (b). *P<0.05 compared with baseline in controls and #P<0.05 compared with baseline in diabetics analyzed by Bonferroni’s multiple comparisons test. Result from two-way analysis of variance: (a) interaction: not significant (NS), diabetes: NS, ZM241385: P<0.05. (b) Interaction: P<0.05, diabetes: NS, CGS21680: NS. Kidney International 2015 87, 109-115DOI: (10.1038/ki.2014.219) Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 4 Measured stop flow pressure and calculated net filtration pressure support regulation of the efferent arteriole by adenosine A2a receptors. This signaling is absent in diabetic rats, but is responsive to an exogenous adeonsine A2a agonist. Micropuncture in control and diabetic rats during baseline and after treatment with either the adenosine A2a antagonist ZM241385 (a) or the adenosine A2a agonist CGS21680 (b). Free flow pressure (PFF) (top), stop flow pressure (PSF) (middle), and calculated net filtration pressure (PNET) (bottom). Compared with baseline analyzed by Bonferroni’s multiple comparisons test. Result from two-way analysis of variance: (a) (PFF) interaction: P<0.05, diabetes: P<0.05, ZM241385: not significant (NS). (PSF) interaction: P<0.05, diabetes: P<0.05, ZM241385: P<0.05. (PNET) interaction: P<0.05, diabetes: P<0.05, ZM241385: P<0.05. (b) (PFF) interaction: NS, diabetes: P<0.05, CGS21680: NS. (PSF) interaction: P<0.05, diabetes: P<0.05, CGS21680: P<0.05. (PNET) interaction: P<0.05, diabetes: NS, CGS21680: P<0.05. Kidney International 2015 87, 109-115DOI: (10.1038/ki.2014.219) Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 5 Adenosine A2a receptor mediated decrease in filtration fraction is nitric oxide dependent. Glomerular filtration rate (a), renal blood flow (b), and filtration fraction (c) in control and diabetic rats during baseline (BL), renal artery infusion of unselective nitric oxide synthase inhibitor (L-NAME), and renal artery infusion of L-NAME in combination with the selective adenosine A2a agonist CGS21680 (L-NAME+CGS21680). *P<0.05 compared with baseline in controls, #P<0.05 compared with baseline in diabetics, †P<0.05 compared with L-NAME in controls, and ‡P<0.05 compared with L-NAME in diabetics analyzed by Bonferroni’s multiple comparisons test. Result from two-way analysis of variance: (a) interaction: not significant (NS), diabetes: P<0.05, treatment: P<0.05. (b) Interaction: NS, diabetes: NS, treatment: P<0.05. (c) Interaction: NS, diabetes: P<0.05, treatment: NS. Kidney International 2015 87, 109-115DOI: (10.1038/ki.2014.219) Copyright © 2015 International Society of Nephrology Terms and Conditions