Role of ADAM17 substrates in Progressive Kidney Disease

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 DESCRIPTION (provided by applicant): Therapies to prevent or treat progressive kidney disease associated with fibrosis are lacking. The overall goal of this application is to evaluate the therapeutic potential of inhibition of ADAM17 or of its substrates in progressive kidney disease and to define molecular mechanisms whereby ADAM17 substrates promote kidney disease progression. Our central hypothesis is that the select proximal tubular ADAM17-cleaved substrates promote progressive kidney disease and that both pathways interact and synergize in their injurious actions. We base this hypothesis on preliminary data in ADAM17 hypomorph mice, in a mouse model with inducible proximal tubule-specific ADAM17 knockout, in human samples and in proximal tubular cells. As compared to controls, both mouse models show strongly reduced inflammation and fibrosis after severe AKI or UUO. The rationale underlying the proposed research is that completion will enable us to understand when pro-fibrotic ADAM17-dependent pathway activation occurs during injury/repair, what ADAM17 substrates and molecular mechanisms are involved, how it compares to standard therapy with RAS inhibition and whether available drugs targeting ADAM17-dependent pathways could be repurposed for the treatment of progressive kidney disease. To test this hypothesis, we propose the following three Specific Aims: Aim 1: Define the role and timing of activation of select ADAM17-dependent pathways in kidney disease progression associated with fibrosis, using severe AKI and UUO in mice as models of fibrotic disease. Here we will compare ADAM17 inhibition and inhibition of select ADAM17 pathways with AT1R blockade (current best CKD therapy) or a combination of these therapies. Aim 2: Test the role of select proximal-tubule released ADAM17 substrates in progressive kidney disease. Aim 3: Define cellular mechanisms of select ADAM17 substrate-induced pro- fibrotic EGFR-pathway activation in tubular cells and fibroblasts. It is anticipated that these Aims will yield the following outcomes: (1) We expect to establish select ADAM17 substrates as critical drivers of kidney fibrosis and highlight translational approaches to inhibit them clinically in humans. (2) We will define molecular mechanisms that allow select ADAM17 substrates to be particularly pro-fibrotic. Such results are expected to fundamentally advance our understanding of progressive kidney disease associated with fibrosis. This contribution is significant because it is expected to have a positiv translational impact because drugs for inhibition of select ADAM17 substrates or their downstream effects are already in clinical use and could be repurposed for kidney disease. The research proposed in this application is innovative, in our opinion, because it represents a new and substantive departure from the status quo - no specific fibrosis therapies available - by shifting focus to new drug targets, ADAM17 and its substrates, for the treatment of progressive kidney disease.