Caspase- 1, formerly known as interleukin-1 beta (IL-1beta) converting enzyme, plays a key role in inflammation and cell death. Caspase-1 processes the pro-inflammatory cytokines IL-1beta and interleukin- 18 (IL- 18) to their mature forms. Caspase-1 and IL-18, but not IL-1beta, are important mediators of ischemic acute renal failure (ARF). This grant investigates the mechanism by which IL-18 contributes to injury in ischemic ARF. lschemic ARF is a common condition in hospitalized patients which continues to have a high mortality rate. Caspase-1 mediated production of IL-18 may contribute to the pathogenesis of ischemic ARF by initiating a series of events which culminates in interstitial neutrophil accumulation and proximal tubular cell (PT) necrosis. The following hypotheses will be investigated: 1) The sites of IL-18 production are the renal endothelium and PT. 2) IL-18 from the endothelium upregulates expression of vascular cell adhesion molecule-1 (VCAM- 1) which facilitates neutrophil adherence to the renal vasculature. 3) IL-18 from the PT enters the interstitium where it induces production of the chemokine macrophage-inflammatory protein-2 (MIP-2) by macrophages. MIP-2 then attracts neutrophils into the interstitium. 4) The entry of neutrophils into the interstitium contributes to the pathogenesis of ischemic ARF. 5) IL- 18 also contributes to renal injury independent of neutrophils. Experiments will be carried out using an in vivo model of ischemia (bilateral renal pedical clamping in mice) as well as an in vitro model (freshly isolated proximal tubules exposed to hypoxia).
