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

摘要 抗体介导性肾小球肾炎(AGN)是自身免疫性肾脏疾病的临床表现。 值得注意的是，在美国，AGN是导致肾功能障碍的第二大原因，占总肾脏的20%-30% 失败案例。对免疫抑制药物的反应通常不充分，并与显著的副作用有关 效果。肾小球和肾小管腔的慢性炎症会导致组织损伤， 最终导致不可逆转的肾功能丧失。新出现的数据表明促炎症细胞因子IL-2 17在AGN发病机制中的作用。IL-17领域的主要焦点一直是IL-17产生细胞如何 而对IL-17下游信号的调节知之甚少。 相关组织细胞类型。我们的新数据显示，在AGN的小鼠模型中，IL-17受体信号 在非造血细胞中是AGN发病所必需的。因此，我们将在这里重点定义IL-17 特定肾细胞类型中的信号机制和结果。了解这一点很重要，因为 组织损伤发生在局部，限制这种损伤的干预措施在临床上具有很高的治疗价值。 以AGN为特征的终末器官损害。具体地说，这项提议的中心是 从两个方面理解转录后调控的分子基础 不同类型的肾细胞、肾小球足细胞和肾小管上皮细胞(RTECs)。我们最近 发现了两种RNA结合蛋白，Regnase-1和Arid5a，它们以相反的方式作用于 负性和正性分别控制IL-17信号转导。与AGN特别相关，这些限制性商业惯例 控制IL-17依赖的Lipocalin-2的表达，Lipocalin-2具有强大的肾脏损伤特性。我们的 中心假说是，Regnase-1通过限制Lipocalin-2的表达来限制AGN的发展。 肾炎肾。在目标1中，我们将确定选择性Regnase-1缺陷对肾脏居民的影响。 足细胞和RTEC。AIM 2将定义参与调节IL-17信号转导的信号事件 小鼠和人类足细胞和RTEC。此外，还将评估治疗小鼠的临床前疗效 通过AGN中的Arid5a抑制剂，我们预测这将允许通过 Regnase-1。这些研究将促进我们对致病的IL-17信号是如何在 肾炎肾能促进终末器官损害。此外，这项工作可能会揭示IL-1中的新药物靶点。 可用于治疗IL-17诱导的其他慢性肾脏终末器官损害的17信号通路 与这种细胞因子有关的疾病。

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.