A Novel Therapeutic Approach to Treat Focal Segmental Glomerulosclerosis (FSGS)

治疗局灶节段性肾小球硬化症 (FSGS) 的新方法

• 批准号: 10513834
• 负责人: Robert Spurney
• 金额: $ 24.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10513834
• 关键词: Address; Adriamycin PFS; Affect; African American population; Albuminuria; Animal Model; Apoptosis; Apoptotic; Atrial Natriuretic Factor; Attenuated; Binding; Blood Circulation; Brain; Brain natriuretic peptide; C-Type Natriuretic Peptide; Calcium; Calcium Signaling; Cells; Characteristics; Cicatrix; Cyclic GMP; Diagnosis; Disease; Disease Progression; End stage renal failure; Endocrine system; Epithelial Cells; Etiology; Focal Segmental Glomerulosclerosis; Funding Opportunities; Generations; Goals; Heart; Heart Atrium; Histologic; Human; Hypertension; Immune system; Incidence; Injury; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Laboratories; Ligands; Mediating; Medicare; Modeling; Mus; NPR2 gene; Natriuretic Peptides; Nephrotic Syndrome; Parietal; Pathway interactions; Patients; Pattern; Peptide Receptor; Pharmacology; Play; Process; Proteinuria; Rare Diseases; Renal glomerular disease; Renin-Angiotensin System; Resistance; Role; Signal Transduction; Source; Stimulus; Therapeutic immunosuppression; United States; antagonist; base; cell type; cost; drug development; experimental study; hemodynamics; in vivo; inhibitor; interest; kidney cell; mouse model; novel; novel therapeutic intervention; novel therapeutics; peptide analog; podocyte; preclinical study; prevent; protective effect; receptor; rho GTP-Binding Proteins; translational potential

FSGS is characterized by segmental scarring of the glomerulus and nephrotic syndrome. Despite current therapies, ~50% of nephrotic patients progress to end stage kidney disease (ESKD) over a decade. As a result, there is much interest in developing new treatments. FSGS is defined by its characteristic histologic pattern, but the disease is caused by multiple, distinct etiologies, which share a final common pathway of podocyte injury and depletion. Because podocytes are terminally differentiated, postmitotic cells, podocytes that are lost cannot be effectively replaced, causing instability and collapse of the glomerular tuft, and disease progression. Treatment is focused on preventing podocyte injury and loss. Accumulating evidence suggests that cGMP signaling is podocyte protective in glomerular diseases. Natriuretic peptides (NPs) potently stimulate cGMP generation in podocytes by binding to NP receptors (NPRs). NPRA binds atrial NP (ANP) and brain NP (BNP), and NPRB binds the C-type NP (CNP). Podocyte specific knockout (KO) of the cGMP generating ANP/BNP receptor, NPRA, augments glomerular injury in proteinuric mouse models, indicating that NPs have podocyte protective actions. A negative regulator of NP actions is the clearance receptor NPRC, which binds and degrades ANP, BNP and CNP. Our preliminary experiments found: 1. Podocytes express NPRA, NPRB and NPRC. 2. NPs protect podocytes from apoptotic stimuli, 3. NPRC is highly expressed in podocytes and limits cGMP generation by locally available NPs, 4. Pharmacologic blockade of NPRC potentiates NPRA- and NPRB-induced cGMP generation in cultured podocytes and in vivo, and 5. Podocyte specific KO of NPRC reduces albuminuria in a mouse model of FSGS. The decrease in albuminuria in podocyte specific NPRC KO mice is unlikely to be mediated by systemic or hemodynamic mechanisms, and suggests a direct podocyte protective effect. Based on these findings, we hypothesized that blocking clearance of NPs by NPRC will elevate NP levels and promote podocyte protective cGMP signaling. Aim 1 will study the effect of podocyte specific KO of NPRC in 1. A mouse model of FSGS created in our laboratory (model 1), and 2. The Adriamycin model of FSGS (model 2). Aim 2 exams pharmacologic blockade of NPRC in model 1 using a novel NPRC antagonist. Current NPRC ligands are peptide analogs of ANP, which are rapidly degraded in the circulation. This novel ligand is resistant to degradation and robustly enhances cGMP generation in vivo compared to currently available NPRC ligands. The proposed studies address the goals of the funding opportunity by "performing proof of concept studies in an animal model of a rare disease". These experiments will establish "proof of concept" and provide the rationale for developing effective, degradation resistant inhibitors of NP clearance. Development of these drugs will provide the basis for preclinical studies using pharmacologic inhibitors of NP clearance to elevate NP levels and cGMP signaling in podocytes and, in turn, reduce glomerular injury in FSGS.

FSGS的特点是肾小球节段性瘢痕形成和肾病综合征。尽管目前 在治疗方面，约50%的肾病患者在十年内进展为终末期肾病(ESKD)。结果, 人们对开发新的治疗方法很感兴趣。FSGS是由其特有的组织学模式定义的，但 这种疾病是由多种不同的病因引起的，这些病因共享足细胞损伤的最终共同途径。 和耗尽。因为足细胞是终末分化的有丝分裂后细胞，所以丢失的足细胞不能 被有效替代，导致肾小球小球不稳定和塌陷，并导致疾病进展。 治疗的重点是预防足细胞损伤和丢失。越来越多的证据表明cGMP 在肾小球疾病中，信号对足细胞具有保护作用。利钠肽(NPs)对cGMP的激活作用 通过与NP受体(NPR)结合在足细胞中产生。NPRA与心钠素(ANP)和脑钠素(BNP)结合， NPRB结合C型NP(CNP)。产生ANP/BNP的cGMP的足细胞特异性敲除(KO) 受体NPRA增加蛋白尿小鼠模型的肾小球损伤，表明NPs有足细胞 保护性行动。NP作用的一个负调节因子是清除受体NPRC，它结合并降解 ANP、BNP和CNP。我们的初步实验发现：1.足细胞表达NPRA、NPRB和NPRC。2. NPS保护足细胞免受凋亡刺激，3.NPRC在足细胞中高表达，并限制cGMP 由当地可用的NPs产生，4.药物阻断NPRC增强NPRA和NPRB诱导的 培养的足细胞和体内cGMP的产生；5.NPRC的足细胞特异性KO减少蛋白尿 在FSGS的小鼠模型中。足细胞特异性NPRC KO小鼠蛋白尿的减少不太可能 由全身或血流动力学机制调节，提示有直接的足细胞保护作用。基座 根据这些发现，我们假设NPRC阻止NPs的清除将提高NP水平并促进 足细胞保护性cGMP信号。目的1研究NPRC对小鼠足细胞特异性KO的影响 本实验室建立的FSGS模型(模型1)和FSGS的阿霉素模型(模型2)。目标2 使用一种新的NPRC拮抗剂在模型1中检测NPRC的药理阻断。目前NPRC的配体是 心钠素的多肽类似物，在循环中迅速降解。这种新型的配基可以抵抗 与目前可用的NPRC配体相比，它可以有效地降解和增强体内cGMP的生成。 拟议的研究通过以下方式解决资助机会的目标：“在 一种罕见疾病的动物模型“。这些实验将建立”概念验证“，并提供 开发有效的、抗降解的NP清除抑制剂的基本原理。发展中的 这些药物将为使用NP清除的药物抑制剂进行临床前研究提供基础。 提高足细胞内NP水平和cGMP信号转导，进而减轻FSGS肾小球损伤。