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Dunlop Prize Lecture and Networking Event

An opportunity for members and non-members to network with scientists from a variety of backgrounds and ages. The second of two lectures by the Society's 2017 Dunlop Prize Lecture winner Dr Neeraj (Bean) Dhaun.

23 May 2018

Abstracts deadline:

Registration deadline:

Dublin, Ireland - View map

  • Overview
  • About the lecturer
  • About the lecture

2017 Dunlop Prize Lecturer, Dr Neeraj (Bean) Dhaun, University of Edinburgh, delivers a lecture on the role of the innate immune system in hypertension and its complications.

The event will be hosted by RCSI Molecular & Cellular Therapeutics (MCT), and Prof. Tracy Robson as Head of department, and Fellows of the Society, Professor David Williams and Professor John Waddington.

Registration

Pre-Registration is necessary.
To Register please email dunlopprize@rcsi.ie
[please state if attending lecture Only Or both events]


Event Timings

Lecture: from 6pm

Venue

Albert Lecture Theatre
RCSI
123 St Stephen's Green
Dublin 2
Ireland

My group’s research focuses on the cardiovascular risk associated with the spectrum of chronic kidney disease (CKD) from early in the disease trajectory through to end-stage renal failure requiring dialysis or kidney transplantation. We perform pre-clinical and clinical pharmacology studies as well as investigating cardiovascular risk at a population level. Our goals are to identify cardiovascular risk early in patients with CKD and, through experimental medicine studies, to explore novel therapies that might reduce this risk and so potentially improve longer-term patient outcomes.

Role of the innate immune system in hypertension and its complications

Hypertension is common. However, its cause remains unclear in the majority of those affected. Recent data suggest that macrophages (Mf)/monocytes contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. However, the effects of ET-1 on Mf biology are not well studied.
 
I have investigated the effects of acute and chronic Mf depletion using the CD11b-DTR mouse on the acute pressor and chronic hypertensive effects of ET-1 infusion. In vitro, Mf ETB receptor function was explored using pharmacological, gene silencing and knockout approaches. In patients with small vessel vasculitis, the impacts of Mf depleting and non-depleting therapies on BP and the ET system were examined.
 
Acute and chronic systemic depletion of Mf resulted in both an augmented acute pressor and chronic hypertensive response to ET-1. Mouse Mf and human monocytes expressed both ETA and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mf with exogenous ET-1 did not polarise Mf phenotype. Interestingly, both mouse Mf and human monocytes cleared ET-1 through ETB receptor mediated dynamin-dependent endocytosis. I confirmed my in vivo and in vitro findings through the generation of novel mice lacking ETB receptors solely on myeloid cells (LysMETB-/-). These mice displayed an exaggerated hypertensive response to chronic angiotensin II infusion, a model that is ET-1 dependent. Finally, in patients who received Mf depleting immunotherapy I have shown that BP is higher and the ET system more activated than in those who received non-depleting therapies.
 
Overall, these data suggest that Mf and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.
 

Perspectives

Hypertension is a costly global health problem, and an important risk factor for the development and progression of chronic kidney disease (CKD). Its aetiology remains unclear in most adults and, despite treatment with multiple antihypertensive agents, most CKD patients fail to reach target BP. My novel data suggest that the immune and ET systems play important roles in BP regulation and provide a rational basis for further investigation into the modulation of these pathways. If successful, they may encourage industry to take a lead in this relatively orphan area, potentially resulting in a more rational prescribing of ET receptor antagonists for hypertension that has developed as part of a multi-system inflammatory disease, with these agents potentially affording broader cardiovascular protection.