LOSS OF KIDNEY FUNCTION BY GLOMERULAR SCLEROSIS

局灶性节段性肾小球硬化和其他肾小球疾病 硬化过程通常进展为肾功能衰竭，伴有蛋白尿和 发现肾小球血流动力学异常。这种硬化症是 由基质的正常胶原成分组成的肾小球 基底膜。我们认为硬化症是一种对 由固有的肾小球细胞产生基质。在系膜， 肌球蛋白扩张可代表系膜细胞肥大。 这可以通过增加肾小球内血压或血流来启动， 通过循环介质或渗入炎症细胞，或通过 上皮细胞局部反应，失去抑制细胞生长的能力 系膜细胞。对于上皮细胞来说，导致 过多的基质(本身或系膜细胞)可能是一种敏感性。 通常不会过滤的蛋白质，因此不会被 上皮细胞。为了将这些元素分开，我们描述了两个 培养的人肾小球细胞类型，系膜细胞呈平滑肌样 细胞和接触抑制的上皮细胞。我们已经展示了他们的 基底膜胶原蛋白的合成。 我们现在将首先通过免疫化学技术建立鉴别 对于维持在非增殖状态的细胞。然后我们将量化 利用分子生物学技术合成胶原蛋白 生物化学。以确定潜在刺激因素的影响 肾小球硬化的发生，是由于基底膜的不受控制的合成 膜成分，我们将考察肌肉介质的作用 肾小球系膜细胞和正常肾小球系膜细胞的收缩和炎症 血浆蛋白和炎症刺激，包括免疫损伤，在 上皮细胞分化和GBM合成。最后，它的影响 这两个单元格将组合在一起，以探索 合作信号在硬化症的发生发展中的作用。预计 了解培养中对肾小球细胞的控制机制将 有助于防止正常肾小球结构的破坏 肾小球硬化和由此导致的灾难性肾功能丧失 在许多肾脏疾病中。

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.