Pericyte-mediated intra-renal blood flow regulation: from brain to kidney

The kidney produces urine by a process of blood filtration and subsequent modification of the filtrate by selective reabsorption and secretion. Kidney blood flow is high, but for filtration rather than metabolism. However, the kidney blood supply must fulfil the needs of highly regulated glomerular filtration, tissue oxygenation and metabolic clearance, as well as the kidney‘s ability to maintain an osmotic gradient (from cortex to medulla) necessary for it to (among other things) concentrate or dilute urine. These requirements impose an unusual structure and arrangement on the intra-renal vasculature, comprising essentially 2 capillary networks in series: the first is glomerular; the second is a linear and U-shaped arrangement of capillaries that forms in the medulla to preserve its high osmolality, while ensuring adequate oxygenation and metabolic clearance. Less is known about the regulation of this unique medullary capillary network, which is the subject of this application. These capillaries are surrounded by specialised contractile cells (pericytes); I propose to identify the receptors and mediators determining their function (and thereby medullary blood flow) using the imaging and electrophysiological approach that I have already successfully developed to study similar capillary structures and local blood flow in the CNS and retina.

Aims: To exploit and extend my recent findings on capillary regulation in the CNS, as well as my knowledge and technical expertise in vascular physiology, to study renal microcirculatory physiology. Specifically, the role and regulation of descending vasa recta pericytes in the control of renal medullary blood flow.
Objectives: My approach will be step-wise and use intact renal tissue. I want to determine the properties of vasa recta pericytes in intact tissue, their role in controlling renal medullary blood flow, and what local vasoactive mediators may be involved, particularly the source and role of ATP and nitric oxide.
Design: I will use freshly isolated intact kidney tissue slices, the isolated perfused kidney and prepare the way, and my training, for longer-term studies in vivo (of the exposed renal papilla), this being my ultimate goal.
Methodology: I will combine advanced imaging techniques like multiphoton confocal microscopy (which is essential for studying intact tissue) with vascular pharmacology and electrophysiology. I will adopt a step-wise approach to my experiments in going from intact tissue slices (with which I have had prior experience) to define receptors, ion channels and agonist pharmacology, to the isolated perfused kidney to investigate changes in medullary blood flow control under various conditions, and eventually to study blood flow changes and regulation in the intact kidney in vivo. My experimental approach will increase in complexity in direct correlation with my understanding of renal blood flow control.
Scientific and medical opportunities: Renal physiology research is under-represented in the UK and particularly studies in renal vascular physiology. Regulation of the renal microcirculation is poorly understood and with recent technical developments, and my own experience and expertise, now is an ideal opportunity (for me) to investigate this problem in some detail in a recognised renal physiology laboratory. The medical implications are potentially very significant. The renal microcirculation plays a critical role in renal diseases like acute renal failure and chronic renal failure resulting from progressive renal ischaemia and fibrosis.