Kidney PCSK9 in nephrotic syndrome

肾病综合征中的肾脏 PCSK9

• 批准号: 10542792
• 负责人: Lionel Claudius Clement
• 金额: $ 34.54万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542792
• 关键词: Affinity; Amiloride; Animal Model; Antibodies; Archives; Biopsy; Blood Circulation; Breeding; Cell Line; Cell surface; Cells; Cholesterol; Confocal Microscopy; Detection; Development; Diabetic Nephropathy; Diagnosis; Disease; Duct (organ) structure; Family; Focal and Segmental Glomerulosclerosis; Gel; Glomerulonephritis; Hepatic; Human; Intestines; Kidney; Kidney Diseases; Link; Liver; Longitudinal Studies; Low Density Lipoprotein Receptor; Mass Spectrum Analysis; Membranous Glomerulonephritis; Modeling; Molecular; Molecular Chaperones; Mus; Nephrosis; Nephrotic Syndrome; Patient Care; Patient Selection; Patients; Pattern; Pharmaceutical Preparations; Phase; Phosphorylation; Plasma; Play; Post-Translational Protein Processing; Proprotein Convertases; Protein Secretion; Proteins; Proteinuria; Puromycin Aminonucleoside; Rattus; Recombinants; Renal glomerular disease; Rodent; Rodent Model; Role; Sampling; Serine Protease; Serum; Sodium; Subtilisins; Sulfate; Testing; Therapeutic; Tissues; Urine; cell cortex; comparison control; db/db mouse; epithelial Na+ channel; gain of function mutation; heart disease risk; hypercholesterolemia; hypocholesterolemia; improved; kidney biopsy; kidney cortex; member; migration; nephrotoxicity; prevent; protein expression; sialylation; standard care; two-dimensional

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.

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， 尿中出现大量蛋白质（蛋白尿）和血浆胆固醇水平升高 （高胆固醇血症）。前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）在肝脏中得到了充分研究， 它与高胆固醇血症的发生有关，但对肾脏与高胆固醇血症之间的联系知之甚少。 PCSK 9和高胆固醇血症。他汀类药物和/或PCSK 9抗体现在被认为是标准治疗， 高胆固醇血症的患者，但这种治疗方法仅在高胆固醇血症患者 建立和不阻止高胆固醇血症的发展。 来自申请人实验室的最近研究表明，PCSK 9在肾脏中表达，主要在皮质中表达。 收集管（CCD）和从CCD分泌的PCSK 9引发肾病患者的高胆固醇血症 综合征事实上，PCSK 9在人局灶性和节段性肾小球硬化症的CCD中表达增加 （FSGS）肾活检与对照相比。在两种FSGS动物模型中也观察到这种现象。 在该提案中，PI将研究肾病综合征高胆固醇血症起源的分子机制， 综合征，并将确定CCD分泌的PCSK 9的特定糖组学谱。它将允许它的检测， 在高胆固醇血症的早期阶段的消耗，以防止或减少进展到既定的 相位 在具体目标1中，申请人将通过共聚焦显微镜研究活检组织中CCD-PCSK 9的表达 来自患有其他肾脏疾病的肾病患者和相应的动物模型。 在特定目标2中，申请人将使用质谱法鉴定特定的翻译后修饰 从肾脏CCD分泌的PCSK 9的谱。LDL受体对不同形式重组体的亲和力 还将评估模拟肝脏或肾脏分泌蛋白的PCSK 9。 在具体目标3中，申请方将研究从细胞中调节CCD-PCSK 9表达及其耗竭的作用。 血浆对肾病综合征持续高胆固醇血症的影响