MACROPHAGES & OTHER MEDIATORS OF INJURY IN EXPERIMENTAL NEPHROTIC SYNDROME

初始肾小球损伤的机制是作为一个 进展为终末期肾病（ESRD）的决定因素 还没有完全被理解。 这一长期目标 我们的建议是研究肾小球的潜在作用， 巨噬细胞和过滤的蛋白质组分， 慢性肾小球损伤的决定因素 实验性肾病综合征三相模型 包括急性肾病，自发恢复，随后 最后是反复的蛋白尿伴肾小球硬化。 关于肾小球巨噬细胞，这些细胞已经被 发现与最初的蛋白尿有关， 然而，肾皮质激素肾病的病理意义， 这些单元的数字调制是未知的。 因为 肾小球巨噬细胞已显示产生细胞因子， 有丝分裂原、有毒氧代谢物和其他血管活性物质， 物质，其目的是评估药理学的作用 (i.e.,氮芥和抗大鼠巨噬细胞抗血清）减少 急性和慢性肾小球疾病中肾小球巨噬细胞数量 损伤时相分析。 此外，尝试 将在体内改变单核细胞/巨噬细胞功能， 饮食策略（例如，高胆固醇血症饮食）和 药理学手段，包括：血栓素合成酶A2和5- 脂氧合酶抑制剂;血栓素A2和LTC 4/LTD 4受体 对手。 预计， 可逆性急性肾病患者单核/巨噬细胞功能 综合征将改变肾小球血流动力学，肾功能， 和肾小球形态学在随后阶段的慢性 氨苯砜肾病 该建议的第二个方面是评估细胞毒性效应 不同过滤蛋白组分对正常大鼠的影响 近端小管悬浮液。 这是基于一个假设， 过量的过滤蛋白在急性肾病引起肾小管 上皮损伤，这一过程可能是不可或缺的， 肾小管间质形态异常， 肾小球疾病 评价肾小管上皮功能 包括：离子转运，线粒体氧化代谢， 膜透性 这些综合研究将有助于澄清 我们对巨噬细胞和过滤蛋白的作用的理解 这些成分是进行性肾小球损伤的决定因素。

The mechanisms whereby initial glomerular injury serves as a determinant for the progression to end-stage renal disease (ESRD) are not completely understood. The long-term objectives of this proposal are to investigate the potential role(s) of the glomerular macrophage and filtered protein constituent fractions as determinants of chronic glomerular injury in aminonucleoside nephrosis; a triphasic model of experimental nephrotic syndrome consisting of acute nephrosis, spontaneous recovery, followed finally by recurrent proteinuria with glomerulosclerosis. In regards to the glomerular macrophage, these cells have been found to vary in relation to the initial proteinuria in aminonucleoside nephrosis; however, the pathologic significance of the numerical modulation, of these cells is unknown. Because the glomerular macrophage has been shown to produce cytokines, mitogens, toxic oxygen metabolites, and other vasoactive substances, it is intended to assess the effect of pharmacologic (i.e., mechlorethamine and anti-rat macrophage antiserum) reduction in glomerular macrophage number on the acute and chronic glomerular injury phases of aminonucleoside nephrosis. Additionally, attempts will be made to alter monocyte/macrophage functions, in vivo, using dietary maneuvers (e.g., hypercholesterolemic diet) and pharmacologic means, including: thromboxane synthetase A2 and 5- lipoxygenase inhibitors; thromboxane A2 and LTC4/LTD4 receptor antagonists. It is anticipated that modulation of monocyte/macrophage function during a reversible acute nephrotic syndrome will alter the glomerular hemodynamics, renal function, and glomerular morphology in subsequent phases of chronic aminonucleoside nephrosis. A second aspect of this proposal is to assess the cytotoxic effect of various filtered protein constituent fractions on normal rat proximal tubule suspensions. This is based on a hypothesis that excess filtered protein during acute nephrosis causes tubular epithelial damage, and this process may be integral to the tubulointerstitial morphologic abnormalities which develop in glomerular disorders. Tubular epithelial functions to be evaluated include: ion transport, mitochondrial oxidative metabolism, and membrane permeability. These combined studies will help to clarify our understanding of the role of macrophage and filtered protein constituents as determinants of progressive glomerular injury.