APOM deficiency contributes to renal failure in glomerular diseases

APOM 缺乏导致肾小球疾病中的肾功能衰竭

基本信息

批准号：
10717305
负责人：
ALESSIA FORNONI
金额：
$ 49.13万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10717305
关键词：
Address Affect Albumins Apolipoproteins Apoptosis Binding Biological Markers Biology Cell Survival Cholesterol Circulation Complex Cyclodextrins Data Devices Disease Progression Disease model Enrollment Enzymes Event Exhibits Experimental Models Extravasation Fatty acid glycerol esters Gene Expression Profile Genotype Goals Grant Hereditary nephritis High Density Lipoproteins Human Impairment In Vitro Injury Kidney Kidney Diseases Kidney Failure Knockout Mice Knowledge Lipids Lipoproteins Liquid substance Metabolic Diseases Metabolism Molecular Molecular Chaperones Mus Mutation Names Nephrotic Syndrome Pathway interactions Patients Pattern Phenotype Physiological Processes Plasma Proliferating Protein Deficiency Proteins Proteinuria Proteomics Recombinants Renal glomerular disease Research Risk Role SPHK1 enzyme Signal Transduction Sphingolipids Sphingosine Sphingosine-1-Phosphate Receptor Therapeutic Therapeutic Effect United States Urine antagonist clinical application clinical development cohort high risk innovation interest kidney cell lipidomics mRNA Expression migration mouse model novel therapeutics outcome prediction overexpression particle podocyte prevent progression risk reverse cholesterol transport sphingosine 1-phosphate sphingosine-1-phosphate lyase translational approach translational study

项目摘要

PROJECT SUMMARY Lipid-induced podocyte injury is an emerging molecular pathway contributing to the progression of glomerular diseases (GDs) of metabolic and non-metabolic origin. Research by others and us has highlighted a role for impaired reverse cholesterol transport (RCT) and altered sphingolipid metabolism in lipid-induced podocyte injury in GDs, yet, a common druggable pathway regulating both RCT and sphingolipid metabolism in podocytes remains to be identified. Among several lipoproteins, Apolipoprotein M (APOM) is mainly located in high density lipoprotein (HDL) particles where it facilitates RCT to HDL but also acts as a chaperone to transport sphingosine-1-phosphate (S1P) through the circulation. S1P signaling occurs through binding of APOM/S1P complexes to S1P receptors (S1PR1-5), which regulate many physiological processes, including migration, proliferation, and cell survival. We recently demonstrated significantly decreased glomerular APOM (gAPOM) mRNA expression in patients with GD enrolled in the NEPTUNE cohort. Our new preliminary data show that decreased gAPOM correlates with decreased plasma APOM (pAPOM), with increased glomerular sphingosine kinase 1 (SPHK1), the enzyme that converts sphingosine to S1P, and S1PR4 expression and with eGFR decline. We observed a similar gene expression pattern in Col4a3 KO mice, a mouse model of GD, and in Col4a3 KO podocytes, which was associated with glomerular/podocyte cholesterol and S1P accumulation due to impaired RCT and activation of S1P/S1PR4 signaling leading to increased apoptosis which was prevented by recombinant human APOM (rhAPOM) treatment. Importantly, the therapeutic effect of rhAPOM in preventing podocyte apoptosis in Col4a3 KO podocytes was superior to SPHK1 or S1PR4 antagonism. Finally, we demonstrate that treatment of human podocytes with exogenous S1P increases podocyte apoptosis and causes albumin leakage in a microfluid device as well as in ApoM deficient Col4a3 KO mice. Based on these observations, we hypothesize that GDs represent a state of gAPOM deficiency causing impaired RCT and activation S1P/S1PR signaling in podocytes, thereby causing lipotoxic podocyte injury. We propose a highly translational approach with three specific aims to 1) investigate if gAPOM deficiency correlates with the activation of glomerular S1P/S1PR signaling, is associated with decreased pAPOM levels and predicts outcomes in patients with GD, 2) to investigate the role of podocyte APOM deficiency on RCT and S1P/S1PR4 signaling, and 3) to investigate the therapeutic potential of recombinant human APOM in an experimental model of GD. If successful, this translational study may lead to the clinical development of APOM as a biomarker in GDs and to the use of recombinant APOM as a novel therapy for GDs.

项目概要脂质诱导的足细胞损伤是一种新兴的分子途径，有助于足细胞的进展代谢性和非代谢性肾小球疾病（GD）。其他人和我们的研究强调了脂质诱导的逆向胆固醇转运 (RCT) 受损和鞘脂代谢改变的作用 GD 中的足细胞损伤，然而，调节 RCT 和鞘脂代谢的常见药物途径足细胞仍有待鉴定。在几种脂蛋白中，载脂蛋白M（APOM）主要位于高密度脂蛋白（HDL）中它促进 RCT 到 HDL 的颗粒，同时也充当运输 1-磷酸鞘氨醇的伴侣（S1P）通过循环。 S1P 信号传导通过 APOM/S1P 复合物与 S1P 受体的结合发生 (S1PR1-5)，调节许多生理过程，包括迁移、增殖和细胞存活。我们最近证明肾小球 APOM (gAPOM) mRNA 表达显着降低 GD 患者被纳入 NEPTUNE 队列。我们的新初步数据显示 gAPOM 下降与血浆 APOM (pAPOM) 减少、肾小球鞘氨醇激酶 1 (SPHK1) 增加相关，将鞘氨醇转化为 S1P 的酶，以及 S1PR4 表达和 eGFR 下降。我们观察到一个 Col4a3 KO 小鼠（GD 小鼠模型）和 Col4a3 KO 足细胞中具有相似的基因表达模式，由于 RCT 和激活受损，与肾小球/足细胞胆固醇和 S1P 积累相关 S1P/S1PR4 信号传导导致细胞凋亡增加，而重组人 APOM 可阻止细胞凋亡（rhAPOM）治疗。重要的是，rhAPOM 在预防 Col4a3 足细胞凋亡方面的治疗作用 KO 足细胞的拮抗作用优于 SPHK1 或 S1PR4。最后，我们证明了人类的治疗具有外源性 S1P 的足细胞会增加足细胞凋亡并导致微流体装置中白蛋白渗漏以及 ApoM 缺陷的 Col4a3 KO 小鼠。基于这些观察，我们假设 GD 代表 gAPOM 缺乏的状态，导致足细胞中的 RCT 和激活 S1P/S1PR 信号传导受损，从而导致脂毒性足细胞损伤。我们提出一种高度转化的方法，具有三个具体目标：1) 研究 gAPOM 缺乏是否相关与肾小球 S1P/S1PR 信号传导的激活有关，与 pAPOM 水平降低相关并预测 GD 患者的结局，2) 研究足细胞 APOM 缺陷对 RCT 和 S1P/S1PR4 的作用信号传导，3) 研究重组人 APOM 在实验模型中的治疗潜力 GD。如果成功，这项转化研究可能会导致 APOM 作为 GD 生物标志物的临床开发以及使用重组 APOM 作为 GD 的新疗法。