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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

基本信息

批准号：
10670414
负责人：
Robert Spurney
金额：
$ 20.13万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670414
关键词：
Address Adriamycin PFS Affect African American population Albuminuria Animal Model Apoptosis Apoptotic Atrial Natriuretic Factor Attenuated Binding Brain natriuretic peptide C-Type Natriuretic Peptide Calcium Calcium Signaling Cells Characteristics Cicatrix Circulation Cyclic GMP Cytoprotection Diagnosis Disease Disease Progression End stage renal failure Endocrine system Epithelial Cells Etiology Focal and Segmental Glomerulosclerosis Funding Opportunities Generations Goals Heart Histologic Human 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 Play Process Proteinuria Rare Diseases Renal glomerular disease Renin-Angiotensin System Resistance Role Signal Transduction Stimulus Therapeutic immunosuppression United States antagonist cell type cost drug development experimental study hemodynamics hypertension control in vivo inhibitor interest kidney cell mouse model novel novel therapeutic intervention novel therapeutics peptide analog pharmacologic podocyte postmitotic preclinical study prevent protective effect receptor rho GTP-Binding Proteins source localization translational potential

项目摘要

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