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.

项目概要摘要主要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，主要的知识差距仍然在于这些药物如何作用于肾脏。知识差距包括 SGLT2 抑制剂如何改变肾脏微血管功能、肾小管系统和肾脏代谢。观察到的特征全肾水平源于微观水平的事件，治疗对肾脏有直接影响微观层面。然而，微观行为不能从整个肾脏的行为中推断出来，必须通过直接观察。这不能在人类身上完成，但可以在大鼠和小鼠的人类肾脏模型中完成使用调查人员擅长的专门技术造成伤害。通过这些方法，本研究将确定 SGLT2 抑制剂对肾脏内部运作的影响。这包括拟议的传出小动脉松弛，这可能对 GFR 没有任何影响，但总是会减少滤过分数并增加 O2 输送到肾脏。研究将确定 SGLT1 作为靶向药物的潜力保护肾脏的新治疗策略。我们将确定SGLT2抑制剂是否存在脱靶对肾脏的影响，有人提出对心脏的影响。我们将比较代谢组学特征这些药物在实验和临床样品中均存在。我们的目标是描绘代谢组学和这些药物在其靶向的肾小管细胞（即早期近端小管）中的蛋白质组学特征，而且将这些效应与暴露于更多葡萄糖的下游肾小管细胞的反应进行比较药物作用。我们的目标是全面了解这些药物如何影响健康和健康的肾脏。患病肾脏更好地了解其治疗益处。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SGLT2 inhibitor dapagliflozin protects the kidney in a murine model of Balkan nephropathy.

SGLT2 抑制剂达格列净可保护巴尔干肾病小鼠模型中的肾脏。

DOI：
发表时间：
2024-02-01
期刊：
影响因子：
0
作者：
Oe, Yuji;Kim, Young Chul;Sidorenko, Viktoriya S;Zhang, Haiyan;Kanoo, Sadhana;Lopez, Natalia;Goodluck, Helen A;Crespo;Vallon, Volker
通讯作者：
Vallon, Volker

Deletion, but not heterozygosity, of eNOS raises blood pressure and aggravates nephropathy in BTBR ob/ob mice.

DOI：
10.1159/000536522
发表时间：
2024-02-01
期刊：
Nephron
影响因子：
2.5
作者：
Sadhana Kanoo;H. Goodluck;Young Chul Kim;Aleix Navarro Garrido;Maria Crespo‐Masip;Natalia Lopez;Haiyan Zhang;Romer A. Gonzalez;Li;Volker Vallon
通讯作者：
Volker Vallon