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

• 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
• 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

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.

项目摘要 脂质诱导的足细胞损伤是一种有助于进展的新兴分子途径 代谢和非代谢起源的肾小球疾病（GDS）。他人和美国的研究强调了 反向胆固醇转运（RCT）和脂质诱导的鞘脂代谢的作用受损 GDS中的足细胞损伤，这是一种调节RCT和鞘脂代谢的常见可药途径 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，但也充当运输鞘氨醇1-磷酸的伴侣 （S1P）通过循环。 S1P信号传导通过APOM/S1P复合物与S1P受体结合而发生 （S1PR1-5），它调节许多生理过程，包括迁移，增殖和细胞存活。 我们最近证明了在 GD患者参加了Neptune队列。我们的新初步数据显示了缺口 与血浆APOM（PAPOM）降低相关，肾小球鞘氨醇激酶1（SPHK1）， 将鞘氨酸转化为S1P的酶和S1PR4表达并随EGFR下降。我们观察到一个 COL4A3 KO小鼠的基因表达模式，GD的小鼠模型和Col4a3 KO Podocytes中的类似基因表达模式，其中 与肾小球/足细胞胆固醇和S1P累积有关，导致RCT受损和激活 S1P/S1PR4信号传导导致凋亡增加，这是由重组人apom所阻止的 （RANAPOM）治疗。重要的是，神奏在防止COL4A3中的足细胞凋亡中的治疗作用 KO足细胞优于SPHK1或S1PR4拮抗作用。最后，我们证明了对人类的治疗 具有外源S1P的足细胞增加了足细胞的细胞凋亡，并在微流体装置中导致白蛋白泄漏 以及APOM缺乏COL4A3 KO小鼠。 基于这些观察结果，我们假设GD代表了引起的GAPOM缺乏状态 RCT受损和激活S1P/S1PR信号传导，从而导致脂肪毒性足细胞损伤。我们 提出一种高度翻译的方法，其三个特定目的是1）研究GAPOM缺陷是否相关 随着肾小球S1P/S1PR信号传导的激活，与Papom水平降低有关，并预测 GD患者的结果，2）研究Podocyte Apom缺乏症对RCT和S1P/S1PR4的作用 信号传导和3）在实验模型中研究重组人APOM的治疗潜力 GD。 如果成功，这项翻译研究可能会导致APOM作为GDS的生物标志物的临床发展 并使用重组APOM作为GD的新型疗法。