Dietary Oxalate and Innate Immunity in Kidney Stone Disease

项目总结： 肾结石(KS)疾病在美国变得越来越普遍，并与系统性 疾病和饮食等生活方式因素。结石形成的一个主要危险因素是尿液升高。 草酸，可从内源性或从饮食中获得。饮食中草酸摄入可能会导致 草酸钙(CaOx)的过饱和，可能会产生这种结石的晶体，在尿液和尿液中形成盐 也许是肾单位。与肾上皮细胞相互作用的CaOx晶体通过释放 刺激单核细胞募集的细胞因子和趋化因子。我们之前报道过患有CaOx的患者 肾结石(CaOx KS)病改变了单核细胞能量代谢，增加了炎症反应。在……里面 此外，我们已经证明，草酸直接破坏细胞能量学和单核细胞氧化还原动态平衡。 健康的受试者。这项研究的长期目标是了解草酸盐如何影响单核细胞和 巨噬细胞在KS病中的免疫代谢目前这项研究的目的是调查 尿结晶、巨噬细胞活化、活性氧(ROS)与尿蛋白原的关系 草酸摄入后的炎症信号通路。中心假设是草酸盐类的干扰 单核细胞线粒体复合体I活性并刺激ROS生成，促炎巨噬细胞 CaOx-KS病的分化和肾脏晶体沉积。目标1将检验草酸盐的假设 通过线粒体复合体I刺激正常人单核细胞反向电子传递(RET) 研究对象。目标2将验证草酸盐介导的晶体尿诱导ROS并破坏 大鼠肾脏巨噬细胞的免疫代谢。到目前为止，还没有研究调查两者之间的联系 CaOx KS病患者的饮食草酸、晶体尿和免疫反应。一种新的尿液检测方法 将研究纳米晶体及其对单核细胞和巨噬细胞的影响。这件事的影响 研究将帮助我们了解单核细胞和巨噬细胞如何对晶体做出反应，并可能识别 评估结石风险、减少结石形成和结石复发的潜在方法。生成的数据 这一建议将促进我们对饮食草酸在KS疾病中免疫细胞的作用的了解 并作为后续R01资金的关键基础。

PROJECT SUMMARY: Kidney stone (KS) disease is becoming more prevalent in the United States and is associated with systemic diseases and lifestyle factors such as diet. A major risk factor for stone formation is an elevation in urinary oxalate, which can be derived endogenously or from the diet. Dietary oxalate intake may induce supersaturation of calcium oxalate (CaOx) which may generate crystals of this stone forming salt in urine and perhaps the nephron. CaOx crystals that interact with renal epithelium activate innate immunity by releasing cytokines and chemokines to stimulate monocyte recruitment. We previously reported that patients with CaOx kidney stone (CaOx KS) disease have altered monocyte cellular energetics and increased inflammation. In addition, we have shown oxalate directly disrupts cellular energetics and redox homeostasis in monocytes from healthy subjects. The long-term goal of this research is to understand how oxalate impacts monocyte and macrophage immunometabolism in KS disease. The objective of the current study is to investigate the relationship between urinary crystals, macrophage activation, reactive oxygen species (ROS), and pro- inflammatory signaling pathways following oxalate consumption. The central hypothesis is oxalate disrupts mitochondrial complex I activity in monocytes and stimulates ROS generation, pro-inflammatory macrophage differentiation, and renal crystal deposition in CaOx KS disease. Aim 1 will test the hypothesis that oxalate stimulates reverse electron transport (RET) through mitochondrial complex I in monocytes from healthy subjects. Aim 2 will test the hypothesis that oxalate mediated crystalluria induces ROS and disrupts macrophage immunometabolism in rat kidneys. No studies to date have investigated the connection between dietary oxalate, crystalluria, and immune responses in CaOx KS disease. A novel approach to assess urinary nanocrystals and their influence on monocytes and macrophages will be investigated. The impact of this research will help us understand how monocytes and macrophages respond to crystals, and may identify potential approaches to assess stone risk, reduce stone formation, and stone recurrence. The data generated from this proposal will advance our knowledge about the role of dietary oxalate on immune cells in KS disease and serve as a key foundation for subsequent R01 funding.