REGULATION OF SERUM PROTEIN COMPOSITION IN NEPHROSIS

肾病综合征的特点是肾小球改变， 渗透选择性导致中间蛋白质的尿损失 分子量（MW）。 虽然白蛋白的合成增加了3%以上， 倍，其血清浓度下降到低于正常的25%， 血清血压（PL）下降。 与白蛋白相反， 许多高分子量蛋白质的浓度在肾病中增加， 为了保护pl，以及在患有遗传性无白蛋白血症（HA）的大鼠中， 无显著尿蛋白损失的动物。 中间体蛋白质 NW（转铁蛋白、γ球蛋白和α球蛋白）在HA中也增加 大鼠，这表明血清PL降低，而不是尿蛋白 白蛋白合成的减少或增加是白蛋白合成增加的刺激。 产生中等和高分子量蛋白质。 我们假设 血清PL调节一系列特定的急性期 反应物蛋白质，并且进一步地，这种控制机制作用于 基因转录水平。 为了验证假设，我们将确定 PL与基团合成速率和催化速率的关系 急性期反应物蛋白质的分子量范围（α 1 AG，α 1 抗胰蛋白酶，转铁蛋白，α 2巨球蛋白），并确定肝 每种mRNA的稳态水平和转录速率， 两种实验动物模型：1）Sprague道利大鼠（SD）， 肾病综合征：由尿蛋白损失引起的PL降低的模型， 2）HA大鼠：无外源蛋白丢失的低pl模型。 我们 将进一步确定是否增加血清PL正常肾病患者 大鼠和HA大鼠通过输入羟乙基淀粉或 聚乙烯吡咯烷酮，抑制这些蛋白质的合成增加， 他们的mRNA。 使用从正常SD和HA分离的培养肝细胞 大鼠，我们将确定PL和合成之间的关系， 白蛋白、转铁蛋白、a1 AG、a1抗胰蛋白酶、a2巨球蛋白和稳定 它们的mRNA的响应的状态浓度和转录速率 不同浓度的白蛋白、PVP和羟乙基淀粉 介质 由于我们已经证明，饮食蛋白质限制， 增强白蛋白基因的表达，当血清PL降低时，我们将 还可以确定蛋白质限制是否调节其他 蛋白质降低血清PL。 如果这些研究表明， 在基因水平上调节一系列蛋白质的合成 转录，我们将启动分子研究，以确定因子（S） 控制着这种反应。

The nephrotic syndrome is characterized by altered glomerular permselectivity causing the urinary loss of proteins of intermediate molecular weight (MW). Although albumin synthesis is increased by over 3 fold, its serum concentration decreases to less than 25% of normal, causing a fall in serum oncotic pressure (pl). In contrast to albumin, the serum concentration of many high MW proteins is increased in nephrosis, helping to defend pl, as well as in rats with hereditary analbuminemia (HA), animals with no significant urinary protein loss. Proteins in intermediate NW (transferrin, gamma globulin and a globulins) are also increased in HA rats, suggesting that reduced serum pl rather than either urinary protein loss or increased albumin synthesis is the stimulus for increased production of both intermediate and high MW proteins. We hypothesize that serum pl regulates the synthesis of a specific array of acute phase reactant proteins , and further that this control mechanism acts at the level of gene transcription. To test the hypothesis we will determine the relationship between pl and the rate of synthesis and catabolism of a group of acute phase reactant proteins of a range of MW's (alpha1AG, alpha1 antitrypsin, transferrin, alpha2 macroglobulin), and determine the hepatic steady state levels and rate of transcription of each species of mRNA in two experimental animal models: 1) Sprague Dawley rats (SD) with the nephrotic syndrome: a model of reduced pl caused by urinary protein loss, and 2) HA rats: a model of reduced pl with no external protein loss. We will further determine whether increasing serum pl to normal in nephrotic rats and rats with HA by the infusion of hetastarch or polyvinylpyrrolodone, suppresses increased synthesis of these proteins and of their mRNA's. Using cultured hepatocytes isolated from normal SD and HA rats, we will determine the relationship between pl and the synthesis of albumin, transferrin, a1AG, a1 antitrypsin, a2 macroglobulin and steady state concentration and rate of transcription of their mRNA's in response to varying concentrations of albumin, PVP and hetastarch in the culture medium. Since we have shown that dietary protein restriction prevents enhanced expression of the albumin gene when serum pl is reduced, we will also determine whether protein restriction modulates the response of other proteins to reduced serum pl. If these studies indicate that serum pl regulates the synthesis of an array of proteins at the level of gene transcription, we will initiate molecular studies to define the factor(s) which control this response.