The role of the cAMP responsive protein AKAP9 in integrin mediated T cell recruitment to the kidney in acute kidney injury

• Applicant: Dr. Jan Herter
• Subject Area: Nephrology ; Anaesthesiology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 227575761

Acute kidney injury (AKI) is characterized by an abrupt loss of kidney function. Despite technological advances, mortality rate of AKI has remained as high as 60% for decades. T-cells, specifically natural killer T-cells, were demonstrated to play critical roles in the pathophysiology of kidney injury as mice deficient in T-cells are protected from AKI. Leukocyte recruitment relies on the activation of ý2-integrins which interact with their counter-receptors to mediate cell arrest and consecutive infiltration of inflamed tissues.Integrin activation via G-protein coupled receptors (GPCR) is regulated by cAMP, an ubiquitous cellular second messenger that is involved in multiple signaling pathways. Even though cAMP was found to inhibit leukocyte integrin activation in response to chemokines, the molecular mechanism for this phenomenon remains elusive. An emerging concept is that A-kinase anchor proteins (AKAPs) serve to compartmentalize cAMP responses by targeting a subset of effector proteins to subcellular structures. In leukocytes, AKAP9 associates with the ý2-integrin leukocyte functioning antigen 1 (LFA-1) and inhibition of the cAMP effector protein kinase A results in increased LFA-1 activation.By using conditional knock-out mice deficient for AKAP9 in CD4+ and CD8+ T-cells this project aims to examine the importance of AKAP9 for cAMP dependent regulation of LFA-1. A comprehensive approach incorporating in vitro analysis of the signaling pathways leading to integrin activation and spatiotemporal distribution of key molecules as well as in vivo studies assessing the recruitment of T-cells to the inflamed vessel wall using intravital microscopy is deployed and the clinical importance of our hypothesis is tested in a murine model of acute kidney failure.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Tanya Mayadas-Norton, Ph.D.