Ischemic acute renal failure is a major cause of native and transplant kidney damage. There is no specific therapy and the underlying mechanisms of ischemic reperfusion injury (IRI) are only partially understood. Our goal is to elucidate the mechanisms underlying renal IRI in order to develop new therapy. Experimental studies from a number of groups, including our own, have shown an important role for inflammation and white cells in renal IRI. Though most of the focus has been on neutrophils, new evidence points toward a role for lymphocytes. We have preliminary data in a mouse model that T cells migrate into postischemic kidney. Furthermore, mice deficient in T cells have significantly reduced renal injury and neutrophil infiltration. We therefore hypothesize that T lymphocytes play an important role in renal IRI. To test this hypothesis, we will use our established mouse model of renal IRI, which includes sensitive inulin clearances to measure glomerular filtration rate. We will evaluate the direct roles of different T cell populations by using mice genetically deficient in select T cells as well as depleting T cells in normal mice. New data demonstrates our ability to manipulate T cell populations using depletion and adoptive transfer techniques. Additional in vivo studies will be performed to compare the role of the neutrophil to that of the T cell in renal IRI. To elucidate the mechanisms of T cell interaction with renal tubular epithelial cells (RTEC) in IRI, we will examine T cell adhesion to RTEC in culture under conditions designed to mimic postischemic sequelae in vivo. We will measure T cell adhesion to RTEC exposed to hypoxia-reoxygenation, chemical anoxia and free-radical generating systems, and determine which adhesion molecules are responsible for T cell-RTEC interactions. Preliminary data demonstrate that these stimuli can significant up-regulate T cell-RTEC adhesion. We will also compare T cell adhesion with RTEC to neutrophils and macrophages. Our studies will potentially lead to important novel findings on the nature of IRI. In addition, due to focus on T cells and translational design of experiments, our data can lead to new therapeutic trials for renal IRI.
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