Hypertension & Renal Theme (HART)
Hypertension & Renal Theme (HART)
HART is a cohesive critical mass of hypertension and renal scientists with >£10 million of current funding from major UK funding bodies & industry partners. Publishing 250 papers in the past 5 years, our prize-winning scientists have a world-leading track record of discovery biology translating through to guideline-changing clinical trials. Our strategy is to identify important molecular mechanisms, focussing on the interactions between hypertension (salt appetite project) (salt-sensitive hypertension project), inflammation & vascular dysfunction (genetic modifiers of kidney disease project) that will eventually lead to fibrosis (kidney injury and resolution project), a common endpoint of all chronic diseases. This focus on early event biology, coupled with enhanced clinical biomarker discovery (retinal optical coherence tomography project), makes preventative intervention a realistic outcome. Parallel interrogation of kidney development using bioengineering makes repair and regeneration a viable alternative for CKD.
Current theme research focus:
(i) Salt, hypertension and cardiovascular risk: new paradigms
Our clinical hypertension research is world leading and underpinned by innovative scientific programmes that have helped shape a new understanding of salt homeostasis, blood pressure control and the role of hormonal/metabolic regulators1 2. Salt accumulation in tissues (vessels, skin, cardiac muscle) creates high salt microenvironments that are detrimental to cardiovascular health. We are using mass spectrometry to map salt microenvironments within the normal and injured kidney and defining the effect of salt on endothelial function, glycocalyx integrity and immune cell activation and polarisation. An integrated physiological approach is defining in vivo how dietary salt affects early-life development of renal dysfunction and how central control of salt-taste activates a systemic hypertensive cascade.
(ii) Prevention & repair of renal injury
We are exploiting novel models of renal injury (including optogenic approaches for targeted cell ablation) and cutting edge technology (e.g. bulk transcriptomics of mRNA & ncRNA from defined cell populations and single cells including renal immune cells) to identify pathways to inflammation and fibrosis and, importantly, those that contribute to repair. Targets are validated in vivo, e.g. miR-214 antagonism to prevent fibrosis, miR-92a to limit glomerular damage, inflammasome targeting. This research targets early interventions on the pathways to fibrosis in patients and we have developed urinary biomarkers to predict renal and cardiac outcomes in diabetes. Developing projects focus on the interaction between kidney and heart disease in pre-clinical models and patient cohorts, and improving cardiovascular risk stratification in renal patients.
(iii) Extra-cellular vesicle signalling in the kidney
This project explores how kidney tubular function is regulated by the microRNA cargo of extracellular vesicles originating from the glomerulus and other regions of the nephron (intra-renal, urinary vesicles), and from distant organs, especially the liver (extra-renal, circulatory vesicles). This is a new physiological mechanism of inter-cellular/inter-organ signalling and represents a new target for treatment of kidney disease and its associated high cardiovascular risk.
(iv) Metabolic receptor pathways to renal vascular injury: P2X7 & GPR81
Structured bioinformatics has associated P2X7 (ATP receptor) and, more recently, GPR81 (lactate receptor) with renal vascular injury. Using hierarchical modelling we have evolved a novel hypothesis of ATP/P2X7 control of macro- and micro-vascular function, validated using in vivo approaches and BOLD-MRI. Moving to renal patients we have placed P2X7 on the interface between endothelial and immune cell function. Further clinical data place P2X7 in a subset of pericytes, a cell at the crossroads between hypoxia, EMT and fibrosis. Genomics shows a strong influence of genotype on P2X7 function, tractable with small molecules/biologics. GPR81 has a similar profile: gene knockout protects against renal injury.
British Heart Foundation, Kidney Research UK, MRC, BBSRC, Medical Research Scotland, Wellcome Trust, Cunningham Trust, Diabetes UK
Current Industrial collaborations:
AZ, GSK, Regulus Therapeutics, AbbVie, Idorsia, Pfizer
Prof David Webb - Theme Lead
Prof Matthew Bailey - Deputy Theme Lead
Dr Laura Denby - ECR Theme Lead