Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
Department of Anatomy, School of Biomedical Science, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin, New Zealand.
Neuroendocrinology. 2022;112(12):1200-1213. doi: 10.1159/000525337. Epub 2022 Jun 2.
Angiotensin (Ang) II signalling in the hypothalamic paraventricular nucleus (PVN) via Ang type-1a receptors (AT1R) regulates vasopressin release and sympathetic nerve activity - two effectors of blood pressure regulation. We determined the cellular expression and function of AT1R in the PVN of a rodent model of polycystic kidney disease (PKD), the Lewis polycystic kidney (LPK) rat, to evaluate its contribution to blood pressure regulation and augmented vasopressin release in PKD.
PVN AT1R gene expression was quantified with fluorescent in situ hybridization in LPK and control rats. PVN AT1R function was assessed with pharmacology under urethane anaesthesia in LPK and control rats instrumented to record arterial pressure and sympathetic nerve activity.
AT1R gene expression was upregulated in the PVN, particularly in corticotrophin-releasing hormone neurons, of LPK versus control rats. PVN microinjection of Ang II produced larger increases in systolic blood pressure in LPK versus control rats (36 ± 5 vs. 17 ± 2 mm Hg; p < 0.01). Unexpectedly, Ang II produced regionally heterogeneous sympathoinhibition (renal: -33%; splanchnic: -12%; lumbar: no change) in LPK and no change in controls. PVN pre-treatment with losartan, a competitive AT1R antagonist, blocked the Ang II-mediated renal sympathoinhibition and attenuated the pressor response observed in LPK rats. The Ang II pressor effect was also blocked by systemic OPC-21268, a competitive V1A receptor antagonist, but unaffected by hexamethonium, a sympathetic ganglionic blocker.
DISCUSSION/CONCLUSION: Collectively, our data suggest that upregulated AT1R expression in PVN sensitizes neuroendocrine release of vasopressin in the LPK, identifying a central mechanism for the elevated vasopressin levels present in PKD.
血管紧张素（Ang）II 通过下丘脑室旁核（PVN）中的血管紧张素 1a 型受体（AT1R）信号转导调节血管加压素释放和交感神经活性 - 这是血压调节的两个效应器。我们确定了多囊肾病（PKD）啮齿动物模型 - 刘易斯多囊肾病（LPK）大鼠中 PVN 中 AT1R 的细胞表达和功能，以评估其对血压调节和 PKD 中血管加压素释放增加的贡献。
荧光原位杂交技术定量测定 LPK 和对照大鼠 PVN 中的 AT1R 基因表达。在 LPK 和对照大鼠中，在乌拉坦麻醉下通过药理学评估 PVN AT1R 功能，这些大鼠被仪器化以记录动脉血压和交感神经活性。
与对照大鼠相比，LPK 大鼠 PVN 中的 AT1R 基因表达上调，特别是在促肾上腺皮质激素释放激素神经元中。PVN 微注射 Ang II 导致 LPK 大鼠的收缩压升高幅度大于对照大鼠（36 ± 5 对 17 ± 2 mm Hg；p < 0.01）。出乎意料的是，Ang II 在 LPK 中产生区域性不均匀的交感神经抑制（肾脏：-33%；内脏：-12%；腰部：无变化），而在对照中没有变化。PVN 预先用洛沙坦（竞争性 AT1R 拮抗剂）处理可阻断 Ang II 介导的肾交感神经抑制，并减轻在 LPK 大鼠中观察到的升压反应。Ang II 的升压作用也被系统给予 OPC-21268（竞争性 V1A 受体拮抗剂）阻断，但不受六烃季铵（交感神经节阻滞剂）的影响。
讨论/结论：总的来说，我们的数据表明，PVN 中 AT1R 表达的上调使 LPK 中的神经内分泌血管加压素释放敏感，这确定了 PKD 中存在的升高血管加压素水平的中枢机制。
