Hypertension is a prevalent yet poorly understood feature of polycystic kidney disease (PKD). Previously we demonstrated that increased glutamatergic neurotransmission within the hypothalamic paraventricular nucleus (PVN) contributes to the hypertension observed in the Lewis Polycystic Kidney (LPK) rat model of PKD. Here we tested the hypothesis that augmented glutamatergic drive to the PVN in LPK rats originates from the forebrain lamina terminalis. Anatomical experiments demonstrated that 38% of PVN-projecting neurons within the subfornical organ (SFO) expressed Fos/Fra, a marker of neuronal activation, in LPK rats while <1% of neurons were Fos/Fra+ in Lewis control rats (P=0.01, n=8). The contribution of the SFO to hypertension and the dependency upon neurotransmission within the PVN was therefore explored in anaesthetised animals. Under these conditions, acute SFO inhibition using isoguvacine produced a greater reduction in systolic blood pressure in LPK compared with Lewis rats (-21±4 vs. -7±2 mmHg, P<0.01; n=10). This could be prevented in the LPK by prior blockade of PVN ionotropic glutamate receptors using kynurenic acid. Furthermore, prior inhibition of the SFO with muscimol normalised the exaggerated depressor response to blockade of ionotropic glutamate receptors in the PVN in the LPK rats (-23±4 vs. -5±5 mmHg, P<0.001; n=14). Collectively, this work shows that projections from the SFO to the PVN drive hypertension in the LPK model of PKD. Following on from this, we explored whether the overactive pathway from the SFO to PVN could be targeted by chronic systemic angiotensin II AT1 receptor antagonism or lowering of plasma hyperosmolality through high-water intake. Neither treatment was able to reduce the activity of this pathway in the LPK (P>0.05), despite producing blood pressure lowering effects (P<0.0001). Our data reveal multiple independent mechanisms contribute to hypertension in PKD, and identify high plasma osmolality, AT1 receptor activation and, importantly, a hyperactive SFO-PVN glutamatergic pathway as potential therapeutic targets.
|Number of pages||1|
|Publication status||Published - 15 Nov 2019|
|Event||Central Cardio-Respiratory Control: Future Directions Conference - Faculty of Medical and Health Sciences University of Auckland, Auckland, New Zealand|
Duration: 18 Nov 2019 → 19 Nov 2019
|Conference||Central Cardio-Respiratory Control: Future Directions Conference|
|Period||18/11/19 → 19/11/19|