Tumor necrosis factor in cisplatin nephrotoxicity

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DESCRIPTION (provided by applicant): This project focuses on the role of tumor necrosis factor alpha(TNFalpha) in the pathogenesis of acute renal failure. Acute renal failure affects about 5% of all hospitalized patients and carries a mortality rate of over 50%. It is unlikely that this high mortality and associated cost will be reduced without a better understanding of the cellular and molecular mechanisms of cell injury. TNFalpha, a proinflammatory cytokine, has been implicated in the pathogenesis of ischemic and toxic acute renal injury. However, the mechanism whereby TNFalpha produces renal failure is unknown. Such knowledge is crucial for the development of approaches to limit renal injury through inhibition of inflammation. Our long-term goal is to reduce the morbidity and mortality associated with acute renal failure through mechanistically targeted interventions. The objective of this application is to determine how inflammatory mechanisms contribute to a clinically relevant form of toxic nephropathy, cisplatin nephrotoxicity. The central hypothesis is that cisplatin increases TNFalpha production in the kidney and that TNFalpha, acting via the TNFR2, provokes an inflammatory response, which contributes to the pathogenesis of cisplatin-induced acute renal failure. We have formulated this hypothesis based on extensive preliminary data. The rationale behind these studies is that once specific inflammatory mediators of cell injury are identified, their production and/or action can be manipulated in innovative approaches to the prevention and treatment of acute renal failure. We plan to test our hypothesis and achieve the objective of this application by pursuing the following three specific aims: 1) Determine the sites of renal TNFalpha production and TNF action in response to cisplatin 2) Determine the mechanisms of cisplatin-induced TNFalpha production 3) Determine the mechanisms of TNFalpha-induced renal injury in cisplatin toxicity. The proposed work is innovative because TNFalpha has not previously been considered important in toxic acute renal failure. Moreover, while TNFalpha is increased in a variety of forms of ARF, the mechanism whereby TNFalpha participates in injury is not known. These studies are significant because they are expected to lead to a formal clinical trial to test the efficacy of currently available anti-TNFalpha treatments for the prevention of cisplatin nephrotoxicity. In addition, these studies will identify potential new targets for clinical interventions. Finally, these results are expected to have significance not only to cisplatin nephrotoxicity, but also to other forms of acute and chronic kidney disease.