Acute renal failure (ARF) is a common disorder with an exceedingly high mortality rate. Inflammation plays an important role in the pathogenesis of ARF. However, the mechanisms by which renal injury activates an inflammatory response and the mechanisms by which innate immune responses are translated into adaptive immune responses in this setting remain poorly understood. The objective of this application is to determine the mechanisms by which insults which lead to renal injury incite an inflammatory response. (TLR) are a family of receptors positioned as a first line of innate defense by recognizing pathogen-associated molecular patterns and endogenous signals of tissue injury. Dendritic cells are specialized migratory antigen presenting cells found as sentinels in peripheral tissues. Our central hypothesis is that crosstalk between injured renal epithelial cells and dendritic cells involving TLR4 results in innate inflammatory responses in ARF. This hypothesis is based on our extensive preliminary data which clearly indicate that dendritic cells and TLR4 play an important role in both ischemic and cisplatin-induced ARF. We plan to test our hypothesis and achieve the objective of this application by pursuing the following specific aims: #1) Identify the pathways by which cell injury leads to an inflammatory phenotype in renal epithelial cells. Our working hypothesis is that the TLR4 pathway in renal epithelial cells is activated during injury and results in the production of pro-inflammatory cytokines;#2) Determine the mechanism of activation of renal dendritic cells during ARF. Our working hypothesis is that under normal conditions renal epithelial cells actively suppress renal dendritic cell activity but that this suppression is overcome by the pro- inflammatory cytokine milieu produced during injury. The proposed work is innovative because the role of dendritic cells and their interactions with renal epithelial cells in ARF is largely unknown. Our expectation is that the results will provide novel insights into the mechanisms whereby initial insults to the kidney provoke inflammation and subsequent exacerbation of structural and functional damage. This information is vital to a more complete understanding of the mechanisms of acute renal injury including endogenous mechanisms which may act to limit injury.
The proposed studies will elucidate the key role of Toll-like receptor 4 and kidney dendritic cells in the induction of the inflammatory phenotype of the kidney during acute injury. These results will be relevant because they are expected to lead to clinical trials to test the efficacy of TLR4 antagonists currently under development and other immunomodulatory strategies for the prevention or treatment of acute renal injury.
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