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

Lead Research Organisation: University of Kent
Department Name: Medway School of Pharmacy

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

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.

Publications

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Hall AM (2011) Multiphoton imaging of the functioning kidney. in Journal of the American Society of Nephrology : JASN

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Kennedy-Lydon T (2015) Nonsteroidal anti-inflammatory drugs alter vasa recta diameter via pericytes. in American journal of physiology. Renal physiology

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Kennedy-Lydon TM (2013) Renal pericytes: regulators of medullary blood flow. in Acta physiologica (Oxford, England)

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Peppiatt-Wildman CM (2013) The evolving role of renal pericytes. in Current opinion in nephrology and hypertension

 
Description CComponents of the innate immune system are mediators of tissue ischemia by altering mitochondrial function and regulating microvessel tone in acute kidney injury
Amount £528,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 05/2012 
End 01/2015
 
Title live kidney slice model 
Description Developed an ex vivo live kidney slice model in which all structural architecture and function mimic the in vivo setting. This model has been used to determine novel regulatory mechanisms of blood flow control and to identify mechanisms of drug-induced nephrotoxicity. The model is now being used to screen potential therapeutics. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Provided To Others? No  
Impact Publications of peer reviewed papers Invited reviews published Invitation to present our data at International Scientific meetings and to individual groups of clinics and drug companies. Now working with Biogen (USA) and Pfizer (USA) utilising this model. Received a renal recognition award from American Physiological Society. 
 
Description Laser Doppler Flowmetry 
Organisation University College London
Department Wolfson Institute for Biomedical Research
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided novel research questions hat could be explored using our collaborators expertise
Collaborator Contribution Provision of technical expertise and equipment and ongoing know how.
Impact Details of data collected described in Nephron Physiology publication
Start Year 2009
 
Description Multiphoton Imaging 
Organisation Royal Free Hospital
Department Centre for Nephrology
Country United Kingdom 
Sector Academic/University 
PI Contribution Equal contribution between myself and colleagues at UCL. Resulted in the development of advanced imaging techniques to measure changes in cellular function in the kidney in real time. Revealed processes occurring during ischemia reperfusion injury. Published research articles and received recognition awards for this work. Resulted in a PhD studentship being funded by a UK charity.
Collaborator Contribution Partners provided equipment use and clinical expertise.
Impact Resulted in 3 research articles detailed in publication section. Funding from St Peters Trust for a PhD studentship. Other grant applications made to KRUK but unsuccessful.
Start Year 2007
 
Description Multiphoton Imaging 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Equal contribution between myself and colleagues at UCL. Resulted in the development of advanced imaging techniques to measure changes in cellular function in the kidney in real time. Revealed processes occurring during ischemia reperfusion injury. Published research articles and received recognition awards for this work. Resulted in a PhD studentship being funded by a UK charity.
Collaborator Contribution Partners provided equipment use and clinical expertise.
Impact Resulted in 3 research articles detailed in publication section. Funding from St Peters Trust for a PhD studentship. Other grant applications made to KRUK but unsuccessful.
Start Year 2007
 
Description Nitric Oxide Study 
Organisation Georgia Health Sciences University
Department Medical College of Georgia
Country United States 
Sector Academic/University 
PI Contribution We are utilising our live kidney slice model to perform complimentary experiments that link renal tubule function with blood flow control.
Collaborator Contribution Provision of compounds to screen and knock out mice in the future.
Impact Abstract submission to Experimental Biology 2013
Start Year 2012
 
Description ischemia reperfusion animal model 
Organisation Barts Health NHS Trust
Department NIHR Biomedical Research Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution none
Collaborator Contribution Provision of animal surgery model of ischemia repercussion
Impact none as of yet
Start Year 2012