ACUTE ISCHEMIC RENAL FAILURE AND KIDNEY-LIVER CROSSTALK

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DESCRIPTION (adapted from the application): Recovery from ischemic renal injury is affected by several cytokines and growth factors including interleukin 10 (IL-10), tumor necrosis factor (TNFa), and hepatocyte growth factor (HGF). Previous studies have focused on production of these molecules by the kidney. However, after severe ischemia, the renal cells may be too damaged to make the molecules necessary to regulate repair. We suggest that such molecules may be produced outside the kidney in the liver. The proposed studies will test the existence of a kidney-liver axis that regulates the response to renal ischemia. We propose that the ischemic kidney produces IL-6, which stimulates hepatic production of IL-10 and induces renal expression of the IL-10 receptor (IL-10R) enabling the kidney to respond to IL-10. This hypothesis is supported by our Preliminary Data, demonstrating that renal ischemia results in renal production of IL-6, followed by expression of IL-10R, and hepatic production of IL-10. Others have shown that hepatic IL-10 is produced by hepatic macrophages; we found that IL-6 stimulates macrophages to produce IL-10. IL-10 has been shown to ameliorate ischemic injury to kidney and other organs. Specific Aim 1 will: 1) determine if IL-6 is the signal from the ischemic kidney that stimulates the liver to produce IL-10; 2) test whether IL-6 is produced in response to hypoxia, or to other cytokines, such as TNFa and IL-1b; 3) test IL-6 production in hypoxic renal tubular cells in vitro; 4) determine the role of the putative hypoxia response element (NF-IL-6); 5) localize sites of IL-6 production in the kidney; and 6) evaluate whether the NF-IL-6 response element activates IL-6 gene in the ischemic kidney and use a gene therapy vector to drive IL-10 expression in the kidney. Specific Aim 2 will: 1) determine IL-10 protein presence in the liver and blood and then 2) determine whether IL-10 inhibits four genes (TNFU, ICAM-1, IL-8 and iNOS) known to exacerbate ischemic renal injury; 3a) investigate IL-10 effects on SOCS-3 (suppressor of cytokine signaling-3) upregulation in the ischemic kidney by comparing SOCS-3 expression in the ischemic kidney of wild-type, IL-10 knockout and anti-IL-10 antibody-treated mice; and 3b) determine if over expression of SOCS-3 in renal cells in vitro inhibits production of TNFa, ICAM-1,IL-8 and iNOS during hypoxia-reoxygenation. This novel proposal is an excellent vehicle for Dr. Kielar to learn new techniques, including organ specific gene therapy and in vivo reporter gene assay. The sponsor for the training grant, Dr. Chris Lu, is an authority on renal immunology and inflammation. The co-sponsor, Dr. Robert Munford, is an expert in physiologically responsive gene therapy. The training program will include formal course work in immunology and immunogenetics to prepare the applicant for an investigative career.