Tulane Hypertension and Renal Center of Excellence and Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States.
Am J Physiol Renal Physiol. 2024 Dec 1;327(6):F946-F956. doi: 10.1152/ajprenal.00160.2024. Epub 2024 Oct 3.
In the proximal tubules of the kidney, angiotensin II (ANG II) binds and activates ANG II type 1 (AT) receptors to stimulate proximal tubule Na reabsorption, whereas atrial natriuretic peptide (ANP) binds and activates natriuretic peptide receptors (NPR) to inhibit ANG II-induced proximal tubule Na reabsorption. These two vasoactive systems play important counteracting roles to control Na reabsorption in the proximal tubules and help maintain blood pressure homeostasis. However, how AT and NPR receptors interact in the proximal tubules and whether natriuretic effects of NPR receptor activation by ANP may be potentiated by deletion of AT (AT) receptors selectively in the proximal tubules have not been studied previously. The present study used a novel mouse model with proximal tubule-specific knockout of AT receptors, PT-, to test the hypothesis that deletion of AT receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Basal blood pressure was about 16 ± 3 mmHg lower ( < 0.01), fractional proximal tubule Na reabsorption was significantly lower ( < 0.05), whereas 24-h urinary Na excretion was significantly higher, in PT- mice than in wild-type mice ( < 0.01). Infusion of ANP via osmotic minipump for 2 wk (0.5 mg/kg/day ip) further significantly decreased blood pressure and increased the natriuretic response in PT- mice by inhibiting proximal tubule Na reabsorption compared with wild-type mice ( < 0.01). These augmented hypotensive and natriuretic responses to ANP in PT- mice were associated with increased plasma and kidney cGMP levels ( < 0.01), kidney cortical NPR and NPR mRNA expression ( < 0.05), endothelial nitric oxide (NO) synthase (eNOS) and phosphorylated eNOS proteins ( < 0.01), and urinary NO excretion ( < 0.01). Taken together, the results of the present study provide further evidence for important physiological roles of intratubular ANG II/AT and ANP/NPR signaling pathways in the proximal tubules to regulate proximal tubule Na reabsorption and maintain blood pressure homeostasis. This study used a mutant mouse model with proximal tubule-selective deletion of angiotensin II (ANG II) type 1 (AT) receptors to study, for the first time, important interactions between ANG II/AT (AT) receptor/Na/H exchanger 3 and atrial natriuretic peptide (ANP)/natriuretic peptide receptor (NPR)/cGMP/nitric oxide signaling pathways in the proximal tubules. The results of the present study provide further evidence for important physiological roles of proximal tubule ANG II/AT and ANP/NPR signaling pathways in the regulation of proximal tubule Na reabsorption and blood pressure homeostasis.
在肾脏的近端小管中，血管紧张素 II（ANG II）与 ANG II 型 1（AT）受体结合并激活后者，以刺激近端小管的钠重吸收，而心房利钠肽（ANP）与利钠肽受体（NPR）结合并激活后者，以抑制 ANG II 诱导的近端小管的钠重吸收。这两个血管活性系统在控制近端小管中的钠重吸收方面发挥着重要的拮抗作用，并有助于维持血压的动态平衡。然而，AT 和 NPR 受体在近端小管中如何相互作用，以及 ANP 激活 NPR 受体是否会通过选择性地在近端小管中删除 AT（AT）受体而增强其利钠作用，这些问题以前尚未得到研究。本研究使用了一种新型的近端小管特异性 AT 受体敲除小鼠模型（PT-），以检验以下假设：即选择性地在近端小管中删除 AT 受体可增强对 ANP 的降压和利钠反应。与野生型小鼠相比，PT-小鼠的基础血压约低 16mmHg（<0.01），近端小管钠重吸收率显著降低（<0.05），而 24 小时尿钠排泄量显著升高（<0.01）。与野生型小鼠相比，通过渗透微型泵输注 ANP（0.5mg/kg/天，ip）2 周后，PT-小鼠的血压进一步显著降低，且利钠反应增强，这是通过抑制近端小管钠重吸收实现的（<0.01）。与野生型小鼠相比，PT-小鼠对 ANP 的这些增强的降压和利钠反应与血浆和肾脏 cGMP 水平升高（<0.01）、肾脏皮质 NPR 和 NPR mRNA 表达增加（<0.05）、内皮型一氧化氮合酶（eNOS）和磷酸化 eNOS 蛋白增加（<0.01）以及尿中一氧化氮排泄增加（<0.01）有关。总之，本研究结果进一步证明了管腔内的 ANG II/AT 和 ANP/NPR 信号通路在调节近端小管钠重吸收和维持血压动态平衡方面发挥着重要的生理作用。本研究使用了一种近端小管特异性缺失血管紧张素 II（ANG II）型 1（AT）受体的突变小鼠模型，首次研究了 ANG II/AT（AT）受体/Na/H 交换器 3 和心房利钠肽（ANP）/利钠肽受体（NPR）/cGMP/一氧化氮信号通路在近端小管中的重要相互作用。本研究结果进一步证明了近端小管 ANG II/AT 和 ANP/NPR 信号通路在调节近端小管钠重吸收和血压动态平衡方面发挥着重要的生理作用。
