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，影响超过36%的糖尿病患者， 美国的有一个医疗需要，以尽量减少糖尿病肾病的影响，因为在后期阶段 存活的唯一选择是透析或肾移植。此应用程序的目标是表征 肾小管周毛细血管与近曲小管细胞间通讯的分子机制。我们 我认为，在糖尿病早期，在肾功能下降之前， 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 肾小管损伤和糖尿病肾病。我们的初步结果已经确定了候选的表面受体 在近端小管中，神经纤毛蛋白，我们发现在秋田小鼠模型中， 1例糖尿病。秋田小鼠患糖尿病，但肾脏疾病的进展不一致，取决于 基因背景。我们将使用129 Sv背景下的秋田小鼠（129 Sv/秋田），因为它们发育肾脏 疾病尚不清楚神经纤毛蛋白是否介导肾小管周围毛细血管和肾小管周围毛细血管之间的细胞-细胞通讯。 近端小管以及糖尿病患者近端小管是否减少。我们的中心假设是："神经纤毛蛋白维持 近曲小管上皮细胞表型通过感知分泌因子从管周毛细血管，因此， 在1型糖尿病129 Sv/秋田小鼠中，这种细胞间通讯途径中断有助于肾脏 损害"。在具体目标1中，我们将确定是否减少近端小管中的神经纤毛蛋白信号传导 导致129 Sv/秋田小鼠的糖尿病肾病。在具体目标2中，我们将确定 神经纤毛蛋白介导的细胞与肾小管周内皮细胞间通讯减少损害近端小管 上皮细胞表型，并有助于糖尿病肾病在129 Sv/秋田小鼠。为了完成这份提案， 我们将采用体外和体内方法相结合的方法，包括尖端技术， 多光子成像、体内基因转导、蛋白质组学和单细胞转录组学。我们希望 为更好地了解导致糖尿病肾病的事件做出了有影响力的贡献， 未来治疗的基础。像我们提出的细胞间通讯途径， 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， 从而为未来竞争性R01提案提供了科学框架。