Investigating the role of the GABA/ glutamate system in the mammalian kidney

GABA is a well established inhibitory neurotransmitter in the CNS, which has an opposing role to its precursor, glutamate, which is an excitatory neurotransmitter. In the CNS, both GABA and glutamate have multifunctional roles that are essential for normal brain functioning, which includes the regulation of cerebral blood flow. Both GABA and glutamate have been shown to induce pericyte-mediated changes in blood flow in the retinae and in the cerebellum, respectively. Pericytes are expressed throughout all mammalian tissue including the kidney, and they are renowned for their contractile nature and their ability to modulate capillary diameter. An increasing number of publications have suggested that both GABA and glutamate might also play a role in the regulation of renal function. All key enzymes associated with GABA/ glutamate metabolism have been localised to the kidney providing the necessary machinery for localised GABA/ glutamate synthesis and metabolism. Despite the collective evidence describing the presence of a GABA/ glutamate system in the kidney, the precise function of such a system requires further clarification. The work presented in this thesis is principally concerned with establishing the physiological role(s) of the GABA and glutamate system in the kidney. This thesis seeks to address this question using a live kidney slice model to investigate pericyte-mediated real-time changes in vasa recta diameter in response to GABA, glutamate and associated compounds. Confocal microscopy techniques were used to confirm the expression of key components in the GABA shunt pathway, in relation to the renal medulla. Data presented here, highlights a novel role for both GABA and glutamate, expressed in both vascular and tubular compartments in the renal medulla, to induce pericyte- mediated regulation of vasa recta diameter, and therefore medullary blood flow. The second aspect of this thesis focuses on determining whether functional GABA receptors exist within renal tissue, focusing specifically on their expression within the cortical collecting duct. Electrophysiological experimental data highlights that functional GABA receptors exist in a renal cell line, which serves to modulate solute transport. In conclusion, this thesis highlights that GABA is able to modulate both vascular and tubular aspects of renal function. While, glutamate, and its co- agonist, glycine, have an opposing effect to GABA, and serve to induce vasodilation. The results of this work highlight new key players that affect renal function, which may be significant in both health and disease.