MACROPHAGES & OTHER MEDIATORS OF INJURY IN EXPERIMENTAL NEPHROTIC SYNDROME

最初的肾小球损伤作为一种 进展为终末期肾病(ESRD)的决定因素 还没有完全被理解。这个项目的长期目标是 建议调查肾小球的潜在作用(S) 巨噬细胞和过滤后的蛋白质组分 氨基核苷对慢性肾小球损伤的影响因素 肾病；实验性肾病综合征的三相模型 由急性肾病组成，自然恢复，其次为 最后是反复蛋白尿伴肾小球硬化。 关于肾小球巨噬细胞，这些细胞已经 发现与最初的蛋白尿有关的不同 氨基核苷肾病；然而，其病理意义 这些细胞的数字调制是未知的。因为 肾小球巨噬细胞已被证明能产生细胞因子， 有丝分裂原、有毒氧代谢物和其他血管活性物质 物质，它的目的是评估药理作用 (即机械氯乙胺和抗大鼠巨噬细胞抗血清)减少 急、慢性肾小球中巨噬细胞的数量 氨基核苷肾病的损害阶段。此外，尝试 将在体内改变单核/巨噬细胞的功能，使用 饮食策略(例如，高胆固醇饮食)和 药理手段，包括：血栓素合成酶A2和5- 脂氧合酶抑制剂；血栓素A2和LTC4/LTD4受体 对抗者。可以预期，调制 可逆性急性肾病患者的单核/巨噬细胞功能 综合征会改变肾小球的血流动力学、肾功能、 慢性肾小球疾病各期肾小球形态的变化 氨基核苷肾病。 这项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 近端小管悬吊。这是基于一种假设，即 急性肾病时过多的过滤蛋白导致肾小管 上皮损伤，这一过程可能是 发生于肾小管间质的形态异常 肾小球疾病。肾小管上皮细胞功能有待评估 包括：离子转运，线粒体氧化代谢，以及 膜通透性。这些综合研究将有助于澄清 我们对巨噬细胞和过滤蛋白作用的认识 作为进行性肾小球损伤决定因素的成分。

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.