Current Perspective on the Location and Function of Gamma- Aminobutyric Acid (GABA) and its Metabolic Partners in the Kidney.

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter located in the mammalian central nervous system, which binds to GABAA and GABAB receptors to mediate its neurological effects. In addition to its role in the CNS, an increasing number of publications have suggested that GABA might also play a role in the regulation of renal function. All three enzymes associated with GABA metabolism; glutamic acid decarboxylase, GABA ?-oxoglutarate transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH) have been localised to the kidney providing the necessary machinery for localised GABA synthesis and metabolism. Moreover GABA receptors have been localised to both tubular and vascular structures in the kidney, and GABA is excreted in urine (~3 ?M) in humans. Despite the collective evidence describing the presence of a GABA system in the kidney, the precise function of such a system requires further clarification. Here we provide an overview of the current renal GABA literature and provide novel data that indicates GABA can act at contractile pericyte cells located along vasa recta capillaries in the renal medulla to potentially regulate medullary blood flow

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

A novel functional role for classic CNS neurotransmitters, GABA, glycine and glutamate, in the kidney: potent and opposing regulators of the renal vasculature

The presence of a renal GABA/glutamate system has previously been described; however, its functional significance in the kidney remains undefined. We hypothesized given its extensive presence in the kidney that activation of this GABA/glutamate system would elicit a vasoactive response from the renal microvessels. Functional data here demonstrate for the first time that activation of endogenous GABA and glutamate receptors in the kidney significantly alters microvessel diameter with important implications for influencing renal blood flow. Renal blood flow is regulated in both the renal cortical and medullary microcirculatory beds via diverse signaling pathways. GABA- and glutamate-mediated effects on renal capillaries are strikingly similar to those central to the regulation of CNS capillaries, that is, exposing renal tissue to physiological concentrations of GABA, glutamate and glycine led to alterations in the way contractile cells, perictyes and smooth muscle cells, regulate microvessel diameter in the kidney. Since dysregulated renal blood flow is linked to chronic renal disease, alterations in the renal GABA/glutamate system, possibly through prescription drugs, could significantly impact long-term kidney function. Key words: GABA, glutamate, Glycine, microvascular function, pericytes. New and Noteworthy: Functional data here offers novel insight into the vasoactive activity of the renal GABA/glutamate system. This data shows that activation of endogenous GABA and glutamate receptors in the kidney significantly alters microvessel diameter. Furthermore, it shows that these antiepileptic drugs are as potentially challenging to the kidney as NSAIDs

TWEAK-Fn14 Signaling Activates Myofibroblasts to Drive Progression of Fibrotic Kidney Disease

The identification of the cellular origins of myofibroblasts has led to the discovery of novel pathways that potentially drive myofibroblast perpetuation in disease. Here, we further investigated the role of innate immune signaling pathways in this process. In mice, renal injury-induced activation of pericytes, which are myofibroblast precursors attached to endothelial cells, led to upregulated expression of TNF receptor superfamily member 12a, also known as fibroblast growth factor-inducible 14 (Fn14), by these cells. In live rat kidney slices, administration of the Fn14 ligand, TNF-related weak inducer of apoptosis (TWEAK), promoted pericyte-dependent vasoconstriction followed by pericyte detachment from capillaries. In vitro, administration of TWEAK activated and differentiated pericytes into cytokine-producing myofibroblasts, and further activated established myofibroblasts in a manner requiring canonical and noncanonical NF-?B signaling pathways. Deficiency of Fn14 protected mouse kidneys from fibrogenesis, inflammation, and associated vascular instability after in vivo injury, and was associated with loss of NF-?B signaling. In a genetic model of spontaneous CKD, therapeutic delivery of anti-TWEAK blocking antibodies attenuated disease progression, preserved organ function, and increased survival. These results identify the TWEAK-Fn14 signaling pathway as an important factor in myofibroblast perpetuation, fibrogenesis, and chronic disease progression