NADPH OXIDASE & MESANGIAL CELL PROLIFERATION & FIBROSIS

终末期肾病（ESRD）在美国的患病率约为30万人，每年花费近150亿美元。这在南卡罗来纳州是一个特别重要的问题，在ESRD的发病率方面，南卡罗来纳州仅次于哥伦比亚特区。从高血压到系统性红斑狼疮等多种疾病都会影响肾脏，最终导致肾功能衰竭。尽管这些疾病在其肾外表现和引发肾损害的特定因素上各不相同，但所有这些疾病的一个关键目标是肾小球，特别是系膜细胞。多功能系膜细胞只能以有限的几种方式对应激作出反应：增殖、收缩、炎症和肾小球基底膜的变化，导致不可逆的纤维化。不幸的是，我们对肾脏疾病中导致系膜细胞激活的机制的理解仍然是初级的。众所周知，慢性肾小球疾病有两个阶段。第一阶段可能是由生长因子和/或毒素水平升高引起的，并与肾小球细胞的增殖有关。这种异常增生活动导致肾系膜细胞扩张。第二阶段表现为细胞外基质（ECM）代谢紊乱，增生减少，导致纤维化。硬化是ECM代谢紊乱的结果，使得生产和降解之间的平衡向生产转移，ECM的组成也发生了变化。这是肾小球硬化症的一个基本特征，无论其病因如何。了解调节增殖和纤维形成的途径可能是制定阻止慢性肾脏疾病进展策略的关键。理想情况下，这些策略将适用于任何初始因素或特定疾病。我们假设在系膜细胞中调节增殖和纤维化信号的一个关键因素是一种叫做NAD(P)H氧化酶的多组分酶，它能产生活性氧（ROS）。我们提出的研究解决了我们在启动和传播慢性肾脏疾病的信号方面的一个重要空白。为了检验这一假设，我们提出了两个具体目标。1号。在培养的系膜细胞模型中，建立系膜细胞NAD(P)H氧化酶在传递增殖和纤维化信号中的核心作用。对比ERK激活途径中已知的组分，确定ERK激活途径中NAD(P)H氧化酶的靶点。2号。探讨NAD(P)H氧化酶产生的ROS在增生性和纤维化肾疾病动物模型中的作用。

End-stage renal disease (ESRD) has a prevalence of about 300,000 people in the U.S. at an annual cost of nearly 15 billion dollars. This is a particularly important concern in S.C., which is second only to the District of Columbia in the incidence of ESRD. Diverse diseases ranging from hypertension to systemic lupus erythematosus can affect the kidney, eventually leading to renal failure. Although those diseases vary in their extrarenal manifestations and in the specific factors that initiate renal damage, a key target for all of these diseases is the glomerulus, particularly the mesangial cell. The multifunctional mesangial cell can only respond to stress in a limited number of ways: proliferation, contraction, inflammation and changes in the glomerular basement membrane that lead to irreversible fibrosis. Unfortunately, our understanding of the mechanisms leading to mesangial cell activation in renal disease is still rudimentary. It is known that there are two phases to chronic glomerular disease. The first phase is probably initiated by increased levels of growth factors and/or toxins and is associated with proliferation of glomerular cells. This abnormal proliferative activity results in cellular expansion in the renal mesangium. The second phase shows decreased proliferation associated with deranged metabolism of extracellular matrix (ECM), leading to fibrosclerosis. Sclerosis is a result of disordered metabolism of ECM such that the balance between production and degradation is shifted in favor of production, and the composition of the ECM is also altered. This is a cardinal feature of glomerulosclerosis regardless of the initiating disease. Understanding the pathways that regulate both proliferation and fibrogenesis may be the key to developing strategies to halt the progression of chronic renal diseases. Ideally, those strategies would be applicable regardless of the initiating factor or specific disease. We hypothesize that a key element that regulates both proliferative and fibrotic signals in mesangial cells is a multicomponent enzyme called NAD(P)H oxidase, which generates reactive oxygen species (ROS). Our proposed studies address an important gap in our knowledge of signals that initiate and propagate chronic renal diseases. In order to test the hypothesis, we propose two specific aims. Number 1. To establish a central role for mesangial cell NAD(P)H oxidase in conveying proliferative and fibrotic signals in cultured mesangial cell models. To identify the target of NAD(P)H oxidase in the pathway of ERK activation vis-a-vis the known components of the ERK activation pathway. Number 2. To establish a role for ROS generated by NAD(P)H oxidase in an animal model of proliferative and fibrotic renal disease.