Underwood Conor F, McMullan Simon, Goodchild Ann K, Phillips Jacqueline K, Hildreth Cara M
Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia.
Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand.
Cardiovasc Res. 2022 Mar 16;118(4):1138-1149. doi: 10.1093/cvr/cvab122.
Hypertension is a prevalent yet poorly understood feature of polycystic kidney disease. Previously, we demonstrated that increased glutamatergic neurotransmission within the hypothalamic paraventricular nucleus produces hypertension in the Lewis Polycystic Kidney (LPK) rat model of polycystic kidney disease. Here, we tested the hypothesis that augmented glutamatergic drive to the paraventricular nucleus in Lewis polycystic kidney rats originates from the forebrain lamina terminalis, a sensory structure that relays blood-borne information throughout the brain.
Anatomical experiments revealed that 38% of paraventricular nucleus-projecting neurons in the subfornical organ of the lamina terminalis expressed Fos/Fra, an activation marker, in LPK rats while <1% of neurons were Fos/Fra+ in Lewis control rats (P = 0.01, n = 8). In anaesthetized rats, subfornical organ neuronal inhibition using isoguvacine produced a greater reduction in systolic blood pressure in LPK vs. Lewis rats (-21±4 vs. -7±2 mmHg, P < 0.01; n = 10), which could be prevented by prior blockade of paraventricular nucleus ionotropic glutamate receptors using kynurenic acid. Blockade of ionotropic glutamate receptors in the paraventricular nucleus produced an exaggerated depressor response in LPK relative to Lewis rats (-23±4 vs. -2±3 mmHg, P < 0.001; n = 13), which was corrected by prior inhibition of the subfornical organ with muscimol but unaffected by chronic systemic angiotensin II type I receptor antagonism or lowering of plasma hyperosmolality through high-water intake (P > 0.05); treatments that both nevertheless lowered blood pressure in LPK rats (P < 0.0001).
Our data reveal multiple independent mechanisms contribute to hypertension in polycystic kidney disease, and identify high plasma osmolality, angiotensin II type I receptor activation and, importantly, a hyperactive subfornical organ to paraventricular nucleus glutamatergic pathway as potential therapeutic targets.
高血压是多囊肾病常见但了解甚少的一个特征。此前，我们证明，下丘脑室旁核内谷氨酸能神经传递增强会在多囊肾病的刘易斯多囊肾（LPK）大鼠模型中引发高血压。在此，我们检验了这样一个假说，即刘易斯多囊肾大鼠室旁核谷氨酸能驱动增强源自终板前脑，这是一个将血源性信息传递至全脑的感觉结构。
解剖学实验显示，终板前脑穹窿下器官中38%投射至室旁核的神经元在LPK大鼠中表达Fos/Fra（一种激活标志物），而在刘易斯对照大鼠中<1%的神经元为Fos/Fra阳性（P = 0.01，n = 8）。在麻醉大鼠中，使用异谷氨酰胺抑制穹窿下器官神经元可使LPK大鼠的收缩压降幅大于刘易斯大鼠（-21±4 vs. -7±2 mmHg，P < 0.01；n = 10），而预先使用犬尿氨酸阻断室旁核离子型谷氨酸受体可预防这种情况。与刘易斯大鼠相比，阻断室旁核离子型谷氨酸受体会使LPK大鼠出现过度的降压反应（-23±4 vs. -2±3 mmHg，P < 0.001；n = 13），预先用蝇蕈醇抑制穹窿下器官可纠正这种反应，但不受慢性全身性血管紧张素II 1型受体拮抗或通过大量饮水降低血浆高渗状态的影响（P > 0.05）；不过这两种治疗方法均能降低LPK大鼠的血压（P < 0.0001）。
我们的数据揭示多种独立机制导致多囊肾病中的高血压，并确定高血浆渗透压、血管紧张素II 1型受体激活，以及重要的是，终板前脑穹窿下器官到室旁核谷氨酸能通路过度活跃作为潜在治疗靶点。
