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.

项目摘要摘要原理肾脏葡萄糖转运蛋白SGLT2的抑制剂已被证明会减慢在存在或不存在糖尿病的情况下，慢性肾脏疾病（CKD）。但是，主要知识差距保留这些药物如何在肾脏上作用。知识差距包括SGLT2抑制剂如何改变肾脏微举行功能，管状系统和肾脏代谢。在从微观层面的事件中出现了全凯尼水平，而治疗的直接作用在微观水平。但是，微观行为不能从整个Kidney行为中推论出来，必须是直接观察到。这不能在人类中完成，但可以在人类肾脏的老鼠和鼠标模型中完成使用专业技术的专业技术受伤。通过这些方法，这项研究将确定SGLT2抑制剂对肾脏内部起作用的影响。这包括建议放松传出动脉，这可能对GFR没有任何影响，但总是会减少过滤分数并增加了O2到肾脏的递送。研究将确定将SGLT1靶向的潜力保护肾脏的新治疗策略。我们将确定SGLT2抑制剂是否具有脱靶在肾脏中的作用，该肾脏已为心脏提出。我们将比较代谢组学的签名这些药物在实验样品和临床样品中。我们的目标是描绘代谢组分和这些药物的蛋白质组学特征在它们靶向的非常管状细胞中，即早期近端小管，也是将这些影响与由于毒品作用。我们的目标是了解这些药物如何影响肾脏的健康和患病的肾脏可以更好地了解其治疗益处。