Role of Kidney Microvasculature-Secreted Factors in Neuropilin Signaling in Proximal Tubule During Diabetic Kidney Disease

糖尿病肾病期间肾脏微血管分泌因子在近曲小管神经毡蛋白信号传导中的作用

• 批准号: 10648746
• 负责人: Paulo Sebastian Caceres
• 金额: $ 57.75万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648746
• 关键词: Address; Affect; Albumins; Albuminuria; Animal Model; Animals; Apoptosis; Biochemical; Biology; Blood Glucose; Blood Vessels; Blood capillaries; Cell Communication; Cells; Cementation; Chronic Kidney Failure; Coculture Techniques; Communication; Complication; Data; Deterioration; Development; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Disease; End stage renal failure; Endothelial Cells; Endothelium; Epithelium; Event; Fibroblast Growth Factor; Fibrosis; Foundations; Functional disorder; Future; Galactose Binding Lectin; Gene Silencing; Genetic; Glucose; Goals; Growth Factor; Histologic; Histology; Homeostasis; Hyperglycemia; Impairment; In Vitro; Insulin-Dependent Diabetes Mellitus; Integrins; Interruption; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Ligand Binding; Ligands; Maintenance; Malignant Neoplasms; Measures; Mediating; Medical; Methods; Mission; Modeling; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neuropilins; Pathology; Pathway interactions; Phenotype; Physiology; Platelet-Derived Growth Factor; Predisposition; Protein Isoforms; Proteinuria; Proteomics; Receptor Protein-Tyrosine Kinases; Renal function; Research; Resistance; Rodent; Role; Semaphorins; Signal Transduction; Societies; Surface; Techniques; Testing; Transduction Gene; Transforming Growth Factor beta; Tubular formation; United States; cadherin 5; candidate identification; capillary bed; career; diabetic; diabetic patient; disease phenotype; effective therapy; endothelial dysfunction; human subject; improved; in vivo; innovation; kidney cell; mouse model; multiphoton imaging; multiphoton microscopy; novel; overexpression; paracrine; plexin; promoter; receptor; renal damage; single-cell RNA sequencing; transcriptomics; type I diabetic; uptake

Project Summary. Diabetic kidney disease is a complication affecting more than 36% of diabetic patients in the United States. There is a medical need to minimize the impact of diabetic kidney disease since at later stages the only options for survival are dialysis or kidney transplant. The goal of this application is to characterize a molecular mechanism of cell-cell communication between kidney peritubular capillaries and proximal tubule. We propose that early in diabetes, before the decline in renal function, the documented deterioration of the kidney microvasculature interrupts the communication with proximal tubule via secreted factors, resulting in proximal tubule damage and diabetic kidney disease. Our preliminary results have identified candidate surface receptors in proximal tubule, neuropilins, that mediate cell signaling we found decreased in the Akita mouse model of type- 1 diabetes. Akita mice develop diabetes, but the progression of kidney disease is inconsistent and depends on the genetic background. We will use Akita mice on 129Sv background (129Sv/Akita) since they develop kidney disease. It is not known whether neuropilins mediate cell-cell communication between peritubular capillaries and proximal tubule and whether this is decreased in diabetes. Our central hypothesis is: “Neuropilins maintain proximal tubule epithelial phenotype by sensing secreted factors from peritubular capillaries, therefore interruption of this cell-cell communication pathway in type-1 diabetic 129Sv/Akita mice contributes to kidney damage”. In Specific Aim 1 we will determine whether decreased neuropilin signaling in proximal tubule contributes to diabetic kidney disease in 129Sv/Akita mice. In Specific Aim 2 we will determine whether decreased neuropilin-mediated cell-cell communication with peritubular endothelium impairs proximal tubule epithelial phenotype and contributes to diabetic kidney disease in 129Sv/Akita mice. To complete this proposal, we will utilize a combination of in vitro and in vivo approaches that include cutting edge techniques like intravital multiphoton imaging, in vivo gene transduction, proteomics and single-cell transcriptomics. We expect to make an impactful contribution towards better understanding the events that lead to diabetic kidney disease, providing the foundations for future therapies. Cell-cell communication pathways like the one we propose have not been considered as mechanism of diabetic kidney disease. Completing this proposal will cement this concept, therefore providing the scientific framework for a competitive future R01 proposal.

项目摘要 糖尿病肾病是一种并发症，影响着超过 36% 的糖尿病患者。 美国从后期开始就存在医学需求，以尽量减少糖尿病肾病的影响。 生存的唯一选择是透析或肾移植。该应用的目标是描述一种情况。 肾小管周围毛细血管和近曲小管之间细胞间通讯的分子机制。 提出在糖尿病早期，在肾功能下降之前，有记录的肾脏恶化 微血管通过分泌因子中断与近端小管的通讯，导致近端小管 我们的初步结果已经确定了候选表面受体。 在近端小管中，神经毡蛋白介导细胞信号传导，我们发现在秋田小鼠模型中减少了- 1. 糖尿病 秋田鼠患上糖尿病，但肾脏疾病的进展并不一致，且取决于 我们将使用 129Sv 背景的秋田小鼠 (129Sv/秋田)，因为它们发育肾脏。 目前尚不清楚神经毡蛋白是否介导管周毛细血管和肾小管周围毛细血管之间的细胞间通讯。 近曲小管以及其在糖尿病中是否减少。我们的中心假设是：“神经毡蛋白维持 通过感测肾小管周围毛细血管的分泌因子来确定近端肾小管上皮表型，因此 1 型糖尿病 129Sv/Akita 小鼠中这种细胞通讯途径的中断有助于肾脏健康 在具体目标 1 中，我们将确定近端小管中的神经毡蛋白信号传导是否减少 在特定目标 2 中，我们将确定是否会导致 129Sv/Akita 小鼠的糖尿病肾病。 神经毡蛋白介导的细胞与管周内皮细胞的通讯受损，近端小管减少 上皮表型并导致 129Sv/Akita 小鼠的糖尿病肾病。 我们将结合使用体外和体内方法，包括体内活体技术等尖端技术 我们期望能够进行多光子成像、体内基因转导、蛋白质组学和单细胞转录组学。 为更好地了解导致糖尿病肾病的事件做出有影响力的贡献， 像我们提出的那样，未来疗法的基础还没有建立。 被认为是糖尿病肾病的机制，完成这项提案将巩固这一概念， 因此，为未来具有竞争力的 R01 提案提供科学框架。