NADPH OXIDASE & MESANGIAL CELL PROLIFERATION & FIBROSIS

终末期肾病（ESRD）在美国约有30万人患病，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，在终末期肾病的发病率方面仅次于哥伦比亚特区。 从高血压到系统性红斑狼疮的各种疾病都可能影响肾脏，最终导致肾衰竭。 尽管这些疾病在其肾外表现和引发肾损伤的特定因素方面各不相同，但所有这些疾病的关键靶点是肾小球，特别是系膜细胞。 多功能系膜细胞只能以有限的方式对应激作出反应：增殖、收缩、炎症和导致不可逆纤维化的肾小球基底膜变化。不幸的是，我们对肾脏疾病中系膜细胞激活的机制的理解仍然是初步的。众所周知，慢性肾小球疾病有两个阶段。 第一阶段可能由生长因子和/或毒素水平的增加启动，并且与肾小球细胞的增殖有关。 这种异常的增殖活性导致肾系膜中的细胞扩张。第二阶段显示与细胞外基质（ECM）代谢紊乱相关的增殖减少，导致纤维硬化。 硬化是ECM代谢紊乱的结果，使得产生和降解之间的平衡向有利于产生的方向转变，并且ECM的组成也改变。 这是肾小球硬化症的一个主要特征，与原发疾病无关。了解调节增殖和纤维化的途径可能是制定阻止慢性肾脏疾病进展的策略的关键。 理想情况下，无论起始因素或特定疾病如何，这些策略都是适用的。我们假设，一个关键因素，调节增殖和纤维化信号在系膜细胞是一种多组分酶称为NAD（P）H氧化酶，它产生活性氧（ROS）。 我们提出的研究解决了我们对启动和传播慢性肾脏疾病的信号的认识中的一个重要空白。 为了验证这一假设，我们提出了两个具体目标。 一号。目的：探讨系膜细胞NAD（P）H氧化酶在系膜细胞增殖和纤维化信号传递中的作用。 通过与ERK激活途径中已知组分的比较，确定ERK激活途径中NAD（P）H氧化酶的靶点。 号2.建立NAD（P）H氧化酶产生的ROS在增生性和纤维化肾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.