The Role of Nrf2 in Proteinuric Chronic Kidney Disease

慢性肾脏疾病(CKD)影响着超过3500万美国人，退伍军人的发病率更高 与普通人群相比，慢性肾脏病的患病率。进行性慢性肾脏病导致终末期 肾脏疾病(ESRD)，一种需要透析或肾脏的完全肾功能衰竭状态 移植以求生存。肾小球疾病是慢性肾脏病的主要原因，是由 通过糖尿病肾病、Alport综合征和局灶性节段性疾病 肾小球硬化。所有这些疾病的特征都是尿蛋白异常。 排泄(蛋白尿)。这是由肾小球滤过屏障功能障碍引起的。 它由内皮细胞、足细胞和它们共享的基底膜组成。 蛋白尿型慢性肾脏病的治疗极其有限，大多数疾病进展缓慢。 而不是治愈它。因此，对蛋白尿型慢性肾脏病尚未得到满足的需求是改进治疗方法。 通过更好地了解肾小球生物学。核因子红系相关基因2(NRF2) 是一种转录因子，可上调细胞保护、抗氧化和解毒基因。 尽管准备在细胞应激时迅速激活，但它受到其抑制剂Kelch- 如正常情况下的ECH相关蛋白1(Keap1)。NRF2可以在药理上 被化合物激活，如巴度松甲基(CDDO-Me)及其类似物CDDO-Im。 最近完成的和正在进行的人体临床试验使用甲基巴多龙治疗 蛋白尿型慢性肾脏病。这些试验一直显示肾小球增加。 滤过率(EGFR)，但这种效应是否会对患者产生整体好处 有争议的。此外，甲基巴度松龙导致糖尿病患者蛋白尿的恶化。 肾脏疾病，但不是阿尔波特综合征。在我们的初步工作中，我们发现基因和 药理学Nrf2增强加重了几个患者的足细胞损伤和蛋白尿 实验性慢性肾脏病小鼠模型的建立。我们的提案将集中在NRF2的利弊 蛋白尿CKD，以更好地了解其在疾病中的作用。在具体目标1中，我们将研究 Nrf2在糖尿病肾病和Alport综合征中是否起不同作用。具体而言 目的：利用条件性基因敲除小鼠，检测Nrf2在不同肾脏细胞中的作用。 在具体目标3中，我们将评估NRF2的剂量或时机如何影响 疾病。令人惊讶的是，几乎没有临床前研究支持Nrf2增强剂在 CKD。需要在动物模型中对Nrf2进行系统和全面的评估 指导临床合理使用Nrf2增强剂。我们的建议书将提供这一关键数据 目的是改善我们退伍军人和所有CKD患者的生活。

Chronic kidney disease (CKD) affects over 35 million Americans, and veterans have a higher prevalence of CKD compared to the general population. Progressive CKD leads to end-stage renal disease (ESRD), a state of complete kidney failure requiring dialysis or renal transplantation for survival. Glomerular diseases are the leading cause of CKD and are caused by diseases such as diabetic nephropathy, Alport syndrome, and focal segmental glomerulosclerosis. All of these diseases are characterized by abnormal urinary protein excretion (proteinuria). This is caused by the dysfunction of the glomerular filtration barrier which is comprised of endothelial cells, podocytes, and their shared basement membrane. Treatments for proteinuric CKD are extremely limited, with most slowing progression of disease rather than curing it. Thus, the unmet need for proteinuric CKD is to improve therapeutics through a better understanding of glomerular biology. Nuclear factor erythroid 2 related 2 (Nrf2) is a transcription factor that upregulates cytoprotective antioxidant and detoxification genes. Although primed to activate quickly during cellular stress, it is restrained by its inhibitor Kelch- like ECH-associated protein 1 (Keap1) under normal conditions. Nrf2 can be pharmacologically activated with compounds such as bardoxolone methyl (CDDO-Me) and its analog CDDO-Im. Recently completed and ongoing human clinical trials utilize bardoxolone methyl to treat proteinuric CKD. These trials have consistently demonstrated an increase in glomerular filtration rates (eGFR), but whether this effect leads to an overall benefit in patients is controversial. Furthermore, bardoxolone methyl caused a worsening of proteinuria in diabetic kidney disease, but not in Alport syndrome. In our preliminary work, we find that genetic and pharmacologic Nrf2 enhancement worsened podocyte injury and proteinuria in several experimental models of CKD in mice. Our proposal will focus on the pros and cons of Nrf2 in proteinuric CKD to better understand its role in disease. In Specific Aim 1, we will examine whether Nrf2 plays differential roles in diabetic kidney disease and Alport syndrome. In Specific Aim 2, we will test the effects of Nrf2 in different kidney cells using conditional knockout mice. In Specific Aim 3, we will evaluate how dose or timing of Nrf2 affects the overall course of disease. Surprisingly, there are few preclinical studies to support the use of Nrf2 enhancers in CKD. A systematic and comprehensive assessment of Nrf2 in animal models is required to guide the rational use of Nrf2 enhancers in the clinic. Our proposal will provide this critical data with the goal of improving the lives of our veterans and of all patients with CKD.