? DESCRIPTION (provided by applicant): The early stage of nephrotoxic serum (NTS)-induced nephritis (NTN) in mice is characterized by excessive inflammation and glomerular barrier dysfunction and represents a good model for human acute glomerulonephritis (GN). Glomerular endothelial and epithelial compartments represent attractive targets for early therapeutic intervention, due to their crucial roles in the recruitment of leukocytes, proteinuria and progressive renal failure. Current therapies aiming to treat or prevent progression of the disease are insufficient and limited, stressing the need for novel therapeutic approaches that control inflammation associated with GN. In this context, the cytokine TNF is an ideal target, since it is critically involved in both human GN and in murine NTN. Unfortunately, attempts to blunt TNF binding to its receptors for the treatment of GN were met with unexpected side effects, including increased risk for bacterial infection. Therefore, therapies that specifically target the deleterios effects of TNF, but leave its beneficial effects intact are desirable. Our preliminary studies indicate that the TIP peptide, which mimics TNF's lectin-like domain and which does not interfere with the ligand's binding to its receptors, interferes with at least two pathways importat in podocyte and glomerular endothelial cells (GEC) demise in NTN. On the one hand, the peptide blunts the p38 pro-inflammatory pathway in GEC, important for the generation of pro-inflammatory mediators, for the induction of eNOS dysfunction and for leukocyte infiltration. On the other hand, TIP peptide protects podocyte barrier function, possibly means by inducing PGE2 generation in podocytes, shown to be protective in NTN. In the early phase of NTN, the peptide blunts systemic generation of TNF, IL-6 and MCP-1, reduces macrophage infiltration, edema formation, restores glomerular filtration rate and synaptopodin expression and abrogates albuminuria. Our central hypothesis is that the TIP peptide protects the kidney against NTN by suppressing TNF-induced activation of pro-inflammatory and barrier-disruptive pathways in GEC and podocytes, respectively, as such blunting leukocyte infiltration and glomerular injury, without interfering with the anti-bacterial actions of the cytokine. In our three specific aims, we will combine in vivo proof-of-concept NTN mouse studies (aims 1 and 2) podocyte- and GEC-based with mechanistic in vitro cell studies (aim 3). We will use unique models and reagents, such as knock-in mice expressing a TNF mutant without functional lectin-like domain (aim 2). Moreover, we will assess local vs. systemic effects of the peptide upon comparing the efficacy of anti-?3(IV) antibody-coupled vs. naked TIP peptide (aim 1A) and testing the peptide in a renal local inflammation model, initiated by endothelial overexpression of transmembrane TNF (aim 1B). Understanding the mechanism of TIP peptide- mediated protective effects against auto-immune GN will advance our knowledge on the inflammatory and anti- inflammatory pathways relevant for nephropathy and will help to conduct clinical trials to determine the efficacy of novel therapeutic peptides against other immune, inflammatory diseases.
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