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，退伍军人的患病率更高。 与普通人群相比，CKD的患病率。进展性CKD导致终末期 肾病（ESRD），一种需要透析或肾功能衰竭的完全肾衰竭状态 移植是为了生存。肾小球疾病是CKD的主要原因， 糖尿病肾病、Alport综合征和局灶性节段性 肾小球硬化所有这些疾病的特点是尿蛋白异常 排泄（蛋白尿）。这是肾小球滤过屏障功能障碍所致 其由内皮细胞、足细胞和它们共有的基底膜组成。 蛋白尿性CKD的治疗方法非常有限，大多数都能减缓疾病的进展 因此，蛋白尿CKD的未满足需求是改善治疗方法， 通过更好地理解肾小球生物学。红细胞核因子2相关2（Nrf 2） 是上调细胞保护性抗氧化剂和解毒基因的转录因子。 虽然在细胞应激时会迅速激活，但它会受到抑制剂Kelch的抑制。 类似于正常条件下的ECH相关蛋白1（Keap 1）。NRF 2可以是 用化合物如甲基巴多索酮（CDDO-Me）及其类似物CDDO-Im活化。 最近完成和正在进行的人类临床试验利用甲基巴多索龙治疗 蛋白尿性CKD。这些试验一致表明，肾小球疾病的增加， 滤过率（eGFR），但这种效应是否会导致患者的总体获益， 争议此外，甲基巴多索龙引起糖尿病患者蛋白尿恶化， 肾脏疾病，但不是Alport综合征。在我们的初步工作中，我们发现基因和 药理学Nrf 2增强加重足细胞损伤和蛋白尿， 小鼠CKD实验模型。我们的建议将集中在Nrf 2的优点和缺点， 蛋白尿性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 Nrf 2是否在糖尿病肾病和Alport综合征中发挥不同的作用。在特定 目的2：利用条件性基因敲除小鼠检测Nrf 2在不同肾细胞中的作用。 在具体目标3中，我们将评估Nrf 2的剂量或时间如何影响整个病程。 疾病令人惊讶的是，很少有临床前研究支持在肿瘤中使用Nrf 2增强剂。 CKD。需要在动物模型中对Nrf 2进行系统和全面的评估， 指导临床合理使用Nrf 2增强剂。我们的提案将提供这些关键数据 目的是改善退伍军人和所有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.