Interaction Between Angiotensin AT1 Receptors and Purinergic P2X Receptors in Regulating the Preglomerular Renal Microcirculation Under Elevated Angiotensin II and High Renal Perfusion Pressure Environments
Authors: Kulthinee Supaporn , Shao Weijian , Franco Martha , Navar L. Gabriel 
Published: June 2021

Angiotensin II (ANG II) exerts a powerful role in the pathogenesis of hypertension and renal injury via activation of angiotensin II type 1 receptors (AT1R). However augmented ANG II levels alone are not sufficient to cause renal microvascular dysfunction in hypertension. Extracellular nucleotides increase in response to increases in arterial pressure and elicit vasoconstriction via P2 purinergic receptors (P2XR and P2YR). In ANG II hypertensive rats, treatment with P2XR antagonists restores glomerular hemodynamics to near normal values and reduces renal injury suggesting interaction between AT1R and P2XR in regulating renal vascular resistance. Accordingly, experiments were performed using the in vitro isolated juxtamedullary nephron preparation to test the hypothesis that P2XR and AT1R have substantial overlap in their actions on afferent arteriolar resistance under elevated ANG II and high renal perfusion pressure (RPP) environments. Afferent arteriolar inside diameters (AAD) were measured in response to increases in perfusion pressure from 100 mmHg to 140 mmHg and superfusion with the P2X1R inhibitor (NF‐449) 1μM, P2X7R inhibitor (A‐438079) 1μM and AT1R inhibitor (RNH‐6270) 1μM. An increase in RPP decreased AAD (12.83±0.54 μm vs. 9.11±0.48μm, n=14, P<0.05) demonstrating intact autoregulatory capability. Treatment with an AT1R inhibitor alone did not restore AAD (9.4±0.56 μm vs. 9±0.51μm, n=5). However vasodilation occurred after treatment with P2X1R inhibitor and AAD returned to values similar to those at RPP 100 mmHg (9.12±0.95 μm vs. 13.22±0.76μm, n=5, P<0.05). Treatment with the P2X7R inhibitor also vasodilated but did not fully restore the AAD to baseline value at RPP 100 mmHg (8.73±1.2 μm vs. 11.53±1.96 μm, n=4, P<0.05). These results support the roles of P2X1R and P2X7R in regulating renal microvascular function in the autoregulatory response to increases in perfusion pressure. Further studies evaluated the acute effects of P2X1R inhibition in the presence of elevated ANG II and increased RPP. The low dose of ANG II (1nM) caused slight decreases in AAD; an increase in RPP caused further decreases in AAD (12.7±0.82 μm, 10.77±0.9 μm, 9.03±0.87 μm, respectively, n=7, P<0.05). Treatment with the P2X1R inhibitor significantly increased AAD to values higher than the value observed at 100 mmHg plus ANG II (11.47±0.62 μm vs.10.77±0.9 μm, P<0.05) but did not return AAD to the baseline value at 100 mmHg (12.7±0.82 μm). The results indicate that renal P2X1 and AT1 receptors are both important in the regulation of AAD during combined elevation in arterial pressure and treatment with ANG II and suggest that P2XR and AT1R have substantial overlap in their actions on afferent arteriolar resistance in kidneys taken from normotensive rats.Support or Funding InformationFunding for this study was provided by the National Institute of General Medical Sciences (NIGMS; CoBRE P30GM103337).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.