Regulation of IL-17 signaling by RNA binding proteins in kidney diseases

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ABSTRACT Antibody-mediated glomerulonephritis (AGN) is a clinical manifestation of autoimmune kidney diseases. Strikingly, AGN is the second leading cause of kidney dysfunction in US, accounting for 20-30% of total renal failure cases. Response to immunosuppressive drugs is often inadequate and associated with significant side effects. Chronic inflammation in the glomerular and tubular compartments of the kidney lead to tissue damage, ultimately causing irreversible loss of renal function. Emerging data implicate the proinflammatory cytokine IL- 17 in the pathogenesis of AGN. The dominant focus in the IL-17 field has been on how IL-17-producing cells are generated, whereas comparatively little is known about regulation of downstream IL-17 signaling in relevant tissue cell types. Our new data show in a mouse model of AGN demonstrate IL-17 receptor signaling in non-hematopoietic cells is required for AGN pathogenesis. Hence, we will focus here on defining IL-17 signaling mechanisms and outcomes in specific renal cell types. Understanding this is important because tissue damage occurs locally, and interventions to limit such damage could be highly valuable clinically to treat the end-organ damage that characterizes AGN. Specifically, this proposal is centered around understanding the molecular basis of post-transcriptional control of mRNA in the context of two distinct kidney cell types, glomerular podocytes and rental tubule epithelial cells (RTECs). We recently identified two RNA binding proteins (RBPs), Regnase-1 and Arid5a, which act in an opposing manner to negatively and positively control IL-17 signaling, respectively. Of particular relevance to AGN, these RBPs control IL-17-dependent expression of Lipocalin-2, which exerts potent kidney-damaging properties. Our central hypothesis is that Regnase-1 restricts AGN development by limiting Lipocalin-2 expression in the nephritic kidney. In Aim 1, we will determine the impact of a selective Regnase-1 deficiency in kidney-resident podocytes and RTECs. Aim 2 will define signaling events involved in regulation of IL-17 signal transduction in mouse and human podocytes and RTECs. Additionally will evaluate the preclinical efficacy of treating mice with an Arid5a inhibitor in AGN, which we predict will allow increased restraint of IL-17 signaling through Regnase-1. These studies will advance our understanding of how pathogenic IL-17 signaling is regulated in the nephritic kidney to promote end-organ damage. Additionally, this work may reveal novel drug targets in the IL- 17 signaling pathway that can be exploited for treating IL-17-driven end-organ damage in other chronic kidney diseases involving this cytokine.