MICA: Investigating ATP regulation and P2X7 blockade in acute renal injury and its long-term complications

Kidney disease is common but often only recognised in more advanced stages. There are many conditions that cause acute kidney injury, some of the most common being conditions in which a patient's immune system becomes chaotic and damages cells and organs. In one of these autoimmune diseases called vasculitis (inflammation of blood vessels), the target organ is the blood vessels (both within and outside the kidney). Many factors lead to the disordered immune response but all involve disruption of the normal regulatory systems that prevent problems in most healthy individuals. We have focussed on one such system in white blood cells, which normally serves to help the immune system respond to infections, but may go wrong in vasculitis;this system is controlled by ATP interacting with particular receptors (called P2X7) on the cell surface and the interaction triggers changes in the way the cells behave. Just as a skin cut can heal completely or form a scar, after inflammatory injury, the kidney can either repair itself or scar, leading to irreversible loss of function. This reduction in kidney function leads to CKD and is accompanied by many other complications including abnormal calcium deposition in blood vessel walls, increasing the risk of heart attacks and stroke. Recent evidence suggests that the same ATP-P2X7 system may be involved in this abnormal calcium deposition. Therefore we want to investigate how ATP and P2X7 are involved in the development of inflammatory kidney diseases and calcium deposition and whether blocking the interaction between ATP and P2X7 could be used as a new target for treatment

ATP signalling through the P2X7 receptor may mediate renal inflammation in AAV, causing acute kidney injury, and accelerated arterial calcification, complicating CKD. ATP levels are normally tightly regulated and a fine balance exists between extracellular ATP production and degradation, mediated by CD39 and CD73 found on numerous cell types but particularly regulatory T-cells. Recent work has highlighted genetic variations in the ATP-degrading ectonucleotidases as significant risk factors for severe vascular calcification. We wish to define the interactions between ATP and its P2X7 receptor and to investigate the potential for abrogating these harmful responses using the AZ P2X7 receptor inhibitor. We will make use of two pre-clinical rat models, one of acute renal vasculitis and glomerulonephritis the other of arterial calcification and progressive renal disease, to mimic the clinical scenarios of acute and chronic kidney disease. We will also investigate mechanisms through which ATP signalling via P2X7 mediates inflammation and arterial calcification using our established in vitro models of aortic ring calcification and granuloma formation. In addition, we will examine expression, genetic and functional differences in CD39, CD73 and P2X7 between healthy subjects and patients with renal inflammation secondary to autoimmune AAV as well as CKD patients with varying degrees of arterial calcification. The data generated should help define the key role played by ATP-P2X7 signalling in inflammatory kidney disease and arterial calcification, allow us to identify and stratify high risk patients and provide a means of personalising treatment using a novel treatment strategy.

The impact of this research project will be clinical and academic. On the academic side the key discovery will be to understand whether ATP signalling through P2X7 is a critical pathway in mediating autoimmunity and vascular calcification. This will also have additional impact on understanding key interactions between immune effectors such as T-cells and macrophage antigen-presenting cells. Further, these studies may help in understanding the interaction between the innate and adaptive immune systems, and explain the link between infections and autoimmune phenomena. These data will be of considerable interest to a wide variety of medical specialities including nephrology, immunology, cardiology and other specialities in which autoimmune disease feature heavily, such as respiratory and gastroenterology.
However, in addition to the academic impact this work could have a significant economic and societal impact. Acute and chronic kidney disease consumes significant healthcare resources (3% of NHS budget is spent on renal replacement services) and leads to many complications affecting other providers. There are further economic costs incurred in managing the considerable disability resulting from accelerated and augmented cardio- and cerebro-vascular disease. The ability to define high risk groups who may benefit from particular therapies or require more intensive monitoring or treatment may enable us to deliver more rational care while minimising the adverse effects of therapies.
Therefore, we believe that this body of work can have immediate and far-reaching impact on the way we assess risk for patients with kidney disease. Moreover, the P2X7 receptor antagonist may provide a novel therapy that could be used at various stages of kidney disease from the early inflammatory response to the downstream complications of scarring and accelerated vascular injury.