LOSS OF KIDNEY FUNCTION BY GLOMERULAR SCLEROSIS

肾小球硬化症导致肾功能丧失

• 批准号: 3241304
• 负责人: Jon I Scheinman
• 金额: $ 11.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-01 至 1993-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3241304
• 关键词: basement membrane; cell differentiation; collagen; hemodynamics; human subject; immunochemistry; kidney cell; mesangium; messenger RNA; muscle cells; myosins; nephrosclerosis; proteinuria; renal failure

Patients with focal segmental glomerular sclerosis and other glomerular sclerotic processes often progress to renal failure, with proteinuria and recognized abnormalities of glomerular hemodynamics. This sclerosis is composed of normal collagenous components of the matrix, the glomerular basement membranes. We envision sclerosis as a loss of control over production of matrix by intrinsic glomerular cells. In the mesangium, expanded myosin can represent smooth muscle mesangial cell hypertrophy. This can be turned on by increased intra-glomerular blood pressure or flow, by circulating mediators or infiltrating inflammatory cells, or by the epithelial cell responding locally, losing its capacity to inhibit the mesangial cell. For the epithelial cell, the stimulus for causing excessive matrix (by itself or by the mesangial cell) can be a sensitivity to proteins that are normally not filtered and therefore not seen by the epithelial cell. To separate these elements, we have characterized two human glomerular cell types in culture, the smooth-muscle like mesangial cells and the contact-inhibited epithelial cells. We have shown their synthesis of basement-membrane collagens. We will now first establish differentiation by immunochemical techniques for cells maintained in a non-proliferative state. We will then quantitate their collagen synthesis by the techniques of molecular biology (mRNA) and biochemistry. To determine the effects of factors potentially inciting the development of glomerular sclerosis, by uncontrolled synthesis of basement membrane components, we will examine the effects of mediators of muscle cell contraction and inflammation on mesangial cells, and that of normal plasma proteins and inflammatory stimuli, including immune injury, on epithelial cell differentiation and GBM synthesis. Finally, the effects of the two cells will be combined, to explore the requirement for a cooperative signal in the development of sclerosis. It is expected that learning the mechanism of control over glomerular cells in culture will help to prevent the obliteration of normal glomerular architecture by glomerular sclerosis and the resulting catastrophic loss of renal function in many renal diseases.

局灶节段性肾小球硬化和其他肾小球疾病患者 硬化过程通常进展为肾衰竭，伴有蛋白尿， 肾小球血流动力学异常。 这种硬化症是 肾小球由基质的正常胶原成分组成， 基底膜 我们认为硬化症是一种对 由肾小球细胞产生基质。 在系膜中， 扩张的肌球蛋白可以代表平滑肌系膜细胞肥大。 这可以通过增加肾小球内血压或流量来开启， 通过循环介质或浸润性炎性细胞，或通过 上皮细胞局部反应，失去了抑制 系膜细胞 对于上皮细胞来说， 过多的基质（本身或系膜细胞）可能是一种敏感性 蛋白质通常不会被过滤，因此不会被 上皮细胞 为了区分这些元素，我们描述了两个 培养的人肾小球细胞类型，平滑肌样系膜细胞 细胞和接触抑制上皮细胞。 我们已经展示了他们的 基底膜胶原的合成。 我们现在将首先通过免疫化学技术建立分化 用于维持在非增殖状态的细胞。 然后我们将定量 通过分子生物学技术（mRNA）合成胶原蛋白， 生物化学 为了确定潜在的刺激因素的影响， 肾小球硬化的发展，通过基底的不受控制的合成 膜组件，我们将研究肌肉介质的影响 肾小球系膜细胞的细胞收缩和炎症，以及正常 血浆蛋白和炎症刺激，包括免疫损伤， 上皮细胞分化和GBM合成。 最后，影响 这两个细胞将被合并，以探索一个 合作信号在硬化症的发展。 预计在 了解控制培养中肾小球细胞的机制， 有助于防止正常肾小球结构的闭塞， 肾小球硬化和由此导致的肾功能的灾难性丧失 许多肾脏疾病。

项目成果

Specialized collagen mRNA and secreted collagens in human glomerular epithelial, mesangial, and tubular cells.

人肾小球上皮细胞、系膜细胞和肾小管细胞中的特殊胶原 mRNA 和分泌胶原。

• DOI: 10.1681/asn.v2101475
• 发表时间: 1992
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Scheinman,JI;Tanaka,H;Haralson,M;Wang,SL;Brown,O
• 通讯作者: Brown,O