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Glomerular and Tubular Function in the Diabetic Kidney

糖尿病肾的肾小球和肾小管功能

基本信息

批准号：
10660770
负责人：
SCOTT Culver THOMSON
金额：
$ 48.6万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660770
关键词：
ADORA2A gene Acid-Base Equilibrium Acute Amino Acids Angiotensins Animal Model Aristolochic Acids Attention Behavior Biochemistry Biological Markers Cells Chronic Chronic Kidney Failure Clinical Complement Dedications Deterioration Diabetes Mellitus Diabetic Nephropathy Diameter Distal Event Exposure to Feedback Filtration Genetic Models Glomerular Capillary Gluconeogenesis Glucose Glucose Transporter Goals Grant Growth Health Heart Histologic Human In Vitro Injury Injury to Kidney Juxtaglomerular Apparatus Kidney Kidney Diseases Knowledge Limb structure Macula densa Maps Measures Mediating Metabolic Metabolic stress Micropuncture Microscopic Modeling Mus NHE1 NOS1 gene Nephrectomy Nephrons Nitric Oxide Synthase Type I Non-Insulin-Dependent Diabetes Mellitus Nutrient Outcome Oxygen Pathway interactions Patients Perfusion Persons Pharmaceutical Preparations Physiology Proteinuria Proteomics Rattus Regional Perfusion Relaxation Renin Reporter Research Research Methodology Research Personnel Rodent Sampling Signal Transduction Sodium Streptozocin Streptozocin Diabetes Stress Surface System Techniques Testing Therapeutic Translating Tubular formation Urine Visualization absorption arteriole base blood pressure reduction constriction diabetic diabetic patient drug action energy balance fatty acid metabolism glomerular filtration glomerular function human data human model human subject improved improved outcome inhibitor insight kidney metabolism metabolomics mouse model new therapeutic target non-diabetic novel novel therapeutic intervention novel therapeutics preservation pressure proteomic signature response sodium-hydrogen exchanger 2 stress reduction symporter

项目摘要

PROJECT SUMMARY ABSTRACT Inhibitors of the principle kidney glucose transporter, SGLT2, have been shown to slow the progression of chronic kidney disease (CKD) in the presence or absence of diabetes mellitus. However, major knowledge gaps remain in how these drugs act on the kidney. Knowledge gaps include how SGLT2 inhibitors alter kidney microvasculature functions, the tubular system, and kidney metabolism. Features that are observed at the whole-kidney level emerge from events at the microscopic level and treatments have their direct effect at the microscopic level. Microscopic behavior, however, cannot be deduced from whole-kidney behavior and must be observed directly. This cannot be done in humans but can be done in rat and mouse models of human kidney injury using specialized techniques at which the investigators are expert. By these methods this research will determine the effects of SGLT2 inhibitors on the inner workings of the kidney. This includes a proposed relaxation of the efferent arteriole, which may not have any effect on GFR but it always reduces filtration fraction and increases O2 delivery to the kidney. Studies will determine potential for targeting of SGLT1 as a new therapeutic strategy to protect the kidney. We will determine whether SGLT2 inhibitors have off-target effects in the kidney, which have been proposed for the heart. We will compare the metabolomics signature of these drugs in both experimental and clinical samples. And we aim to delineate the metabolomic and proteomic signature of these drugs in the very tubular cells they target, i.e., the early proximal tubule, but also compare these effects with responses in downstream tubular cells exposed to more glucose as a consequence of drug action. Our goal is an integrated understanding how these drugs impinge on the kidney in the healthy and diseased kidney to better understand their therapeutic benefits.

项目总结摘要主要的肾脏葡萄糖转运蛋白SGLT2的抑制剂已被证明可以减缓糖尿病的进展。存在或不存在糖尿病的慢性肾病(CKD)。然而，主要的知识差距继续研究这些药物对肾脏的作用。知识空白包括SGLT2抑制剂如何改变肾脏微血管功能、肾小管系统和肾脏新陈代谢。观察到的特征全肾水平产生于微观水平的事件，治疗在微观层面。然而，微观行为不能从全肾行为中推断出来，必须直接观察到的。这不能在人类身上完成，但可以在人类肾脏的大鼠和小鼠模型上完成。使用调查人员擅长的专门技术进行伤害。通过这些方法，本研究将确定SGLT2抑制剂对肾脏内部工作的影响。这包括一项拟议的传出小动脉的松弛，这可能不会对GFR有任何影响，但它总是减少滤过并增加氧气向肾脏的输送。研究将确定将SGLT1作为一种保护肾脏的新治疗策略。我们将确定SGLT2抑制剂是否有偏离靶点对肾脏的影响，已被提出对心脏的影响。我们将比较新陈代谢组学特征这些药物在实验和临床样本中都有。我们的目标是描绘新陈代谢和这些药物在其靶标的肾小管细胞中的蛋白质组特征，即近端小管的早期，但也将这些影响与下游肾小管细胞因接触更多葡萄糖而产生的反应进行比较毒品行动。我们的目标是全面了解这些药物是如何影响健康和以更好地了解其治疗效果。