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Hypothalamic control of blood pressure in polycystic kidney disease
thesisposted on 2022-03-28, 10:10 authored by Conor Francis Underwood
Polycystic kidney disease (PKD) is characterised by the progressive accumulation of multiple bilateral renal cysts that threaten body-fluid homeostasis and glomerular filtration. In PKD patients, the development of hypertension and baroreflex dysfunction both contribute to a high risk of cardiovascular mortality, but the underlying mechanisms are poorly understood. This thesis examined the hypothesis that altered signalling within the hypothalamus and elevations in extracellular fluid osmolality contribute to hypertension and baroreflex dysfunction in a rat model of PKD, the Lewis Polycystic Kidney (LPK) rat. The first goal of this thesis was to determine whether the ongoing activity of neurons in the hypothalamic paraventricular nucleus (PVN), a structure that regulates arterial pressure through multiple neural and humoral outputs, contributes to the maintenance of hypertension and baroreflex dysfunction in LPK rats in early and advanced stages of the disease. Acute pharmacological experiments in anaesthetised animals showed that an early increase in the glutamatergic excitation of PVN neurons maintains hypertension, but not baroreflex dysfunction, in LPK animals. This study also suggested that vasopressin release maintains a component of the hypertension in anaesthetised LPK rats but is independent of PVN neuronal activity and might therefore involve the supraoptic nucleus. However, additional work showed that while supraoptic nucleus vasopressin neurons are more active in LPK rats, chronic systemic inhibition of V1A receptors is not anti-hypertensive. Further studies examined the source of elevated PVN glutamatergic tone in LPK rats. The first hypothesis examined was that the local signalling of angiotensin II, a critical regulator of PVN glutamatergic tone, is enhanced in LPK rats. It was shown that the sensitivity but not tonicity of the angiotensin II type 1 receptor (AT1R) is enhanced in LPK rats and that its activation preferentially drives vasopressin release rather than sympathetic outflow via an indirect interaction with PVN astrocytes. Subsequent work determined whether heightened PVN glutamatergic tone is produced by a greater ongoing discharge of glutamatergic afferents in LPK rats. It was demonstrated that the subfornical organ (SFO), a sensory structure that detects plasma angiotensin II and osmolality levels, contains more activated PVN-projecting neurons in LPK animals and is the primary source of enhanced glutamatergic drive to the PVN in this disease model. However, PVN glutamatergic tone was not reduced by chronic suppression of AT1R (with pharmacology) or plasma hyperosmolality (via high-water intake). High-water intake nevertheless provided novel cardiovascular benefits in LPK rats, including an improvement in hypertension and cardiac baroreflex function. These experiments further our understanding of the origins of cardiovascular dysfunction in PKD, highlighting a SFO-PVN neuronal pathway as a novel therapeutic target to manage hypertension. The work encourages the clinical investigation into whether a prescribed increase in water consumption protects against the development of cardiovascular disease in PKD patients.