HHU StartMedizinische FakultätIRTG 1902PeoplePrincipal InvestigatorsProject 11 - Schrader: Role of Pannexin 1 in ATP-induced purinergic signaling in cardiac and kidney fibroblasts during tissue injury

Project 11

Role of Pannexin 1 in ATP-induced purinergic signaling in cardiac and kidney fibroblasts during tissue injury

Prof. Dr. med. Jürgen Schrader

Dept. of Molecular Cardiology

Background: Chronic kidney disease (CKD) is a recognized risk multiplier for the development of cardiovascular disease. This suggests that there is considerable distant organ effect in which there is a bidirectional relationship between heart and kidney. Understanding this relationship can provide clues to therapeutic approaches that target primary organ injured but distant organs as well in order to reduce overall mortality. The purine nucleoside adenosine is involved in many physiological and pathophysiological events and can be formed extracellularly by ecto-5´-nucleotidase (CD73). Adenosine signals through G-protein coupled adenosine receptors (A1R, A2aR, A2bR, A3R) and mediates anti-inflammatory effects through A2aR and proinflammatory effects through A2bR in various experimental models.

Previous work: The Schrader lab has shown that deletion of CD73 in mice alters thromboregulation and augments the vascular inflammatory response (Koszalka et al 2004). In a model of wire-induced injury (carotid artery), CD73-derived adenosine protects against vascular inflammation and neointima formation by activating A2aR. In CD4(+) T-cells, adenosine formed by CD73 tonically inhibits active NF-κB, thereby modulating via A2aR activation the release of proinflammatory cytokines/chemokines (Romio et al. 2011). More recently, CD73 on granulocytes and T-cells was found to be an important factor in the healing process of myocardial infarction and that lack of CD73 promotes arteriogenesis (Boring et al. 2013).
The Okusa lab demonstrated that CD4(+) iNKT cells play a pivotal role in initiating lung injury, inflammation, and neutrophil recruitment after IR via an IL-17A-dependent mechanism (Sharma et al. 2011). Regulatory T cells were shown to contribute to the protective effect of ischemic preconditioning (Kinsey et al.2010) but the absence of adenosine generation (CD73-deficient Tregs) or adenosine responsiveness (A2aR-deficient Tregs) led to inhibition of Treg function (Kinsey et al. 2012). In the kidney, A2aR activation reduces glomerular proteinuria by preserving the normal structure of podocytes, slit diaphragms, and actin cytoskeleton (Awad et al. 2008). Recently dendritic cells were shown to be tolerized with adenosine A2AR agonist which attenuates acute kidney injury (Li et al. 2012).

Aims: Given the complementary expertise of both laboratories in heart (Schrader) and kidney (Okusa) disease and the synergistic background in adenosine metabolism, function and signaling, the following hypothesis will be tested:  Heart failure after transverse aortic constriction (TAC) leads to activation of the immune response and injury in the kidney. Conversely, acute ischemia-reperfusion injury (IRI) to the kidney leads to activation of the immune response in the heart. Toward this end we will address the time course of immune cell infiltration into the heart after myocardial and kidney injury. Similarly, the impact of heart failure on kidney function will be assessed. The analysis of heart and kidney function will be accompanied by cytokine/chemokine levels in plasma, and the expression of CD73 and A2aR and A2bR on infiltrating immune cells will be assessed. Both, local and distant organ tissue inflammation, microcirculatory flow in vivo will be measured with 19F-MRI and contrast enhanced ultrasound. By monitoring short and long term mortality we will evaluate the therapeutic potential of an A2bR antagonist in a pre-clinical setting. We will determine specificity of this compound by the use of A2aR and A2bR deficient mice.  We will also examine in vivo target organ effect through specific disruption of A2aR, A2bR and CD73s.

Publications

Sung, S. J., Li, L., Huang, L., Lawler, J., Ye, H., Rosin, D. L., Vincent, I. S., Le, T. H.,
Yu, J., Görldt, N., Schrader, J., and Okusa, M. D. (2017) Proximal Tubule CD73 Is Critical in
Renal Ischemia-Reperfusion Injury Protection. J Am Soc Nephrol 28, 888-902

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