Hemolytic-uremic syndrome (HUS), a common cause of acute renal failure in children, is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. HUS is caused by Shiga-toxin producing E.coli of serotype O157:H7. Accumulated evidence from small animals and primates suggests that HUS is essentially a severe inflammatory disease that results from the direct effects of circulating IPS and Shiga toxin in kidneys. Although it has been established that glomerular endothelia are primary targets of Shiga toxin, macrophages appear to be additional targets that may serve to amplify the inflammatory responses. The evidence suggests that kidneys of humans and small animals display substantial differences in the tissue distribution of Gb3, the receptor for Shiga toxins. Also complicating the study of the direct inflammatory effects of LPS and Stx in the kidneys of experimental animals is the expression of increased levels of circulating cytokines, which may contribute to the inflammatory responses of the kidneys. In order to study the direct and indirect effects of Stx and LPS in a human-relevant system, I propose studies focused on precision-cut slices of human kidney in vitro. I will identify the profile of gene transcripts whose expression is increased by Stx and LPS in human kidney slices and will measure the temporal sequence of their increased expression. Inhibitors of relevant signaling pathways (MAP kinases and NFkappaB) will determine the contribution of these pathways to the development of inflammatory responses in human kidney slices. The ligands that are secreted by kidney sections in response to Stx and LPS will be identified, and their ability to elicit inflammatory responses in naive kidney slices will be determined. To investigate the potential involvement of macrophages in the development of HUS, these cells will be depleted from human kidney slices prior to exposure of slices to Stx and LPS. Taken together, these studies should contribute to an understanding of mechanisms by which Stx and LPS induce inflammatory responses in human kidneys. ? ? ?
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