Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University Health Science Center, New Orleans, Louisiana.
Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand.
Am J Physiol Renal Physiol. 2020 Jun 1;318(6):F1400-F1408. doi: 10.1152/ajprenal.00602.2019. Epub 2020 Apr 20.
In ANG II-dependent hypertension, ANG II activates ANG II type 1 receptors (ATRs), elevating blood pressure and increasing renal afferent arteriolar resistance (AAR). The increased arterial pressure augments interstitial ATP concentrations activating purinergic P2X receptors (P2XRs) also increasing AAR. Interestingly, P2XR and P2XR inhibition reduces AAR to the normal range, raising the conundrum regarding the apparent disappearance of ATR influence. To evaluate the interactions between P2XRs and ATRs in mediating the increased AAR elicited by chronic ANG II infusions, experiments using the isolated blood perfused juxtamedullary nephron preparation allowed visualization of afferent arteriolar diameters (AAD). Normotensive and ANG II-infused hypertensive rats showed AAD responses to increases in renal perfusion pressure from 100 to 140 mmHg by decreasing AAD by 26 ± 10% and 19 ± 4%. Superfusion with the inhibitor P2XRi (NF4490; 1 μM) increased AAD. In normotensive kidneys, superfusion with ANG II (1 nM) decreased AAD by 16 ± 4% and decreased further by 19 ± 5% with an increase in renal perfusion pressure. Treatment with P2XRi increased AAD by 30 ± 6% to values higher than those at 100 mmHg plus ANG II. In hypertensive kidneys, the inhibitor ATRi (SML1394; 1 μM) increased AAD by 10 ± 7%. In contrast, treatment with P2XRi increased AAD by 21 ± 14%; combination with P2XRi plus P2XRi (A438079; 1 μM) increased AAD further by 25 ± 8%. The results indicate that P2XR, P2XR, and ATR actions converge at receptor or postreceptor signaling pathways, but P2XR exerts a dominant influence abrogating the actions of ATRs on AAR in ANG II-dependent hypertension.
在血管紧张素 II 依赖性高血压中，血管紧张素 II 激活血管紧张素 II 型 1 受体（ATRs），升高血压并增加肾入球小动脉阻力（AAR）。增加的动脉压会增加间质 ATP 浓度，激活嘌呤能 P2X 受体（P2XRs），进一步增加 AAR。有趣的是，P2XR 和 P2XR 抑制可将 AAR 降低至正常范围，这就提出了一个难题，即 ATR 的影响似乎消失了。为了评估 P2XR 与 ATR 之间在介导慢性血管紧张素 II 输注引起的 AAR 增加方面的相互作用，使用分离的血液灌注髓旁肾单位制备物进行的实验允许观察入球小动脉直径（AAD）。正常血压和血管紧张素 II 输注的高血压大鼠显示出肾灌注压从 100 增加到 140mmHg 时 AAD 的反应，通过降低 AAD 26±10%和 19±4%。用 P2XRi（NF4490；1μM）超滤液可增加 AAD。在正常血压肾脏中，血管紧张素 II（1nM）的超滤液使 AAD 降低 16±4%，并在肾灌注压增加时进一步降低 19±5%。用 P2XRi 处理可使 AAD 增加 30±6%，达到高于 100mmHg 加血管紧张素 II 的水平。在高血压肾脏中，抑制剂 ATRi（SML1394；1μM）增加 AAD 10±7%。相比之下，用 P2XRi 处理可使 AAD 增加 21±14%；与 P2XRi 联合使用 P2XRi（A438079；1μM）可进一步使 AAD 增加 25±8%。结果表明，P2XR、P2XR 和 ATR 作用在受体或受体后信号通路汇聚，但 P2XR 发挥主导作用，消除了血管紧张素 II 依赖性高血压中 ATR 对 AAR 的作用。
