Kidney PCSK9 in nephrotic syndrome

摘要/摘要(最多30行)： 肾病综合征是人类肾小球疾病的主要表现，而患有这种疾病的患者 在尿液中出现大量蛋白质(蛋白尿)和血浆胆固醇水平升高 (高胆固醇血症)。枯草杆菌前蛋白转换酶9(PCSK9)在肝脏中得到了很好的研究 它与高胆固醇血症的发生有关，但对肾脏之间的联系知之甚少。 PCSK9和高胆固醇血症。他汀类药物和/或PCSK9抗体现在被认为是治疗 患者患有高胆固醇血症，但这种治疗方法只能治疗一次高胆固醇血症 已经建立，并且不能预防高胆固醇血症的发展。 申请人实验室最近的研究表明，PCSK9在肾脏中表达，主要在皮质 集合管及其分泌的PCSK9引发肾病患者高胆固醇血症 综合症。事实上，在人类局灶性和节段性肾小球硬化症中，PCSK9在CD中的表达增加 (FSGS)肾活检与对照组比较。在FSGS的两个动物模型中也注意到了这一现象。 在这项建议中，PI将研究肾病患者高胆固醇血症的分子机制。 症状，并将确定特定的糖代谢特征的CD分泌的PCSK9。它将允许它的检测和 在高胆固醇血症的早期阶段消耗以防止或减少进展到已建立的 相位。 在具体目标1中，申请者将通过共聚焦显微镜研究活组织中ccd-PCSK9的表达。 来自肾病患者的其他肾脏疾病和相应的动物模型。 在具体目标2中，申请人将使用质谱学来识别特定的翻译后修饰 肾细胞癌分泌的PCSK9的图谱。不同形式重组人低密度脂蛋白受体的亲和力 模仿肝脏或肾脏分泌蛋白的PCSK9也将被验证。 在具体目标3中，申请者将研究调控CCD-PCSK9表达的效果及其从 血浆对肾病综合征患者持续性高胆固醇血症的影响

Summary / Abstract (max 30 lines): Nephrotic syndrome is a major manifestation of human glomerular disease, and patients with this condition develop large amounts of protein in the urine (proteinuria) and elevated levels of plasma cholesterol (hypercholesterolemia). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is well studied in the liver where it is implicated in the development of hypercholesterolemia but little is known about the link between kidney PCSK9 and hypercholesterolemia. Statins and/or PCSK9 antibodies are now considered the standard care for patients with hypercholesterolemia but this therapeutic approach only treats hypercholesterolemia once it is established and does not prevent the development of hypercholesterolemia. Recent studies from the applicant’s lab suggest that PCSK9 is expressed in the kidney, mainly in the cortical collecting duct (CCD) and that PCSK9 secreted from the CCD initiates hypercholesterolemia in nephrotic syndrome. In fact, PCSK9 expression is increased in the CCD in human focal and segmental glomerulosclerosis (FSGS) kidney biopsies compared to controls. This phenomenon was also noted in two animal models of FSGS. In this proposal, the PI will study molecular mechanisms of the origin of hypercholesterolemia of nephrotic syndrome and will identify the specific glycomic profile of CCD-secreted PCSK9. It will allow its detection and depletion during the early phase of hypercholesterolemia to prevent or reduce progression to the established phase. In Specific Aim 1, the applicant will study by confocal microscopy, the expression of CCD-PCSK9 in biopsies from nephrotic patients with other kidney diseases and corresponding animal models. In Specific Aim 2, the applicant will use mass spectrometry to identify the specific post-translational modification profile of PCSK9 secreted from the kidney CCD. The affinity of LDL receptor for different forms of recombinant PCSK9, that mimic liver or kidney secreted proteins, will also be assed. In Specific Aim 3, the applicant will study the effect of modulating CCD-PCSK9 expression and its depletion from plasma on sustained hypercholesterolemia in nephrotic syndrome.