Transcriptional Regulation of Natriuetic Sensitivity in Diabetes Mellitus

糖尿病钠敏感性的转录调控

• 批准号: 8150648
• 负责人: Patience O Obih
• 金额: $ 14.51万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150648
• 关键词: 2,4-thiazolidinedione; Accounting; Adverse effects; Amiloride; Antidiabetic Drugs; Atherosclerosis; Attenuated; Blood; Blood Glucose; Blood Pressure; Cause of Death; Centers for Disease Control and Prevention (U.S.); Chronic; Coronary heart disease; Creatinine; Dehydration; Diabetes Mellitus; Diabetic mouse; Diagnosis; Diet; Disease; Dyslipidemias; Edema; End stage renal failure; Excretory function; Furosemide; Future; Genes; Glucose; Goals; Grant; Hydrochlorothiazide; Hyperglycemia; Hyperlipidemia; Hypertension; Impairment; Insulin Resistance; Ions; Kidney; Kidney Diseases; Knowledge; Lead; Life; Ligands; Measures; Metabolic Diseases; Modeling; Molecular; Mus; Nephrons; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; PPAR gamma; Partner in relationship; Patients; Peripheral; Peripheral Vascular Diseases; Peroxisome Proliferator-Activated Receptors; Pilot Projects; Pioglitazone; Plasma; Play; Prevention; Principal Investigator; Progressive Disease; Renal Hypertension; Renal function; Research; Response Elements; Retinal Diseases; Role; Sodium; Sodium Chloride; Sodium-Hydrogen Antiporter; Sodium-Potassium-Chloride Symporters; Testing; Thiazolidinediones; Time; Transcriptional Regulation; Treatment Protocols; Tubular formation; United States; Universities; Urine; Work; World Health Organization; base; carbohydrate metabolism; cardiovascular risk factor; cost; db/db mouse; diabetic; diabetic patient; health disparity; in vivo; indexing; insight; insulin sensitizing drugs; lipid metabolism; meetings; peroxisome; prevent; protein metabolism; receptor; research study; saluretic; statistics; sugar; symporter; thiazide; urinary

DESCRIPTION (provided by applicant): Estimates from the World Health Organization indicate there are some 130 million diagnosed diabetics in the world, a figure that is predicted to increase to 300 million by 2025. Diabetes mellitus is a metabolic disorder characterized by hyperglycemia and is associated with abnormalities in carbohydrate, fat and protein metabolism resulting in chronic complications including microvascular, macrovascular and neuropathic problems (Oki et al, 2002). Type 2 diabetes is associated with a number of cardiovascular risks including dyslipidemia and hypertension. It is the leading cause of end-stage renal disease (ESDR) which manifests as disturbances in the ability of the kidneys to handle sodium. The thiazolidinediones (TZDs) have been introduced for the treatment of type 2 diabetes. These agents are ligands for peroxisome proliferator activated gamma receptors (PPAR3) and are used in type 2 diabetes since they work by reducing glucose level through decreasing insulin resistance. In our previous study, we defined a role for PPAR1 in sodium handling by the kidney and our results showed that deletion of PPAR1 gene caused a defective Na-Cl cotransporter (NCC) activity as evidenced by a reduced hydrochlorothiazide-sensitive sodium excretion. Based on these observations, we hypothesized that sodium handling is impaired in type 2 diabetes and that PPAR1 gene offers protection from the sodium impairment. Because PPAR3 and PPAR1 share the same peroxisome response elements and can be transactivated by the same ligands, we hypothesize therefore, that PPAR3 will play a defined role in sodium handling in type 2 diabetes. To achieve this goal, we will be using db/db mice and PPAR ligand, pioglitazone to dissect the involvement of PPAR3 in sodium handling in type 2 diabetes. In the first set of experiments, the diabetic, db/db -/- mice will be challenged with a sodium load in diet and the extent of sodium excretion will be evaluated. In another set of experiments, we will examine the role of pioglitazone in in vivo natriuretic mechanisms in type 2 diabetes by evaluating the differential sensitivity of ion transporters in the nephron to hydrochlorothiazide, amiloride, or furosemide, as indices of activity of sodium chloride co-transporter (NCC), sodium hydrogen exchanger (NHE) and sodium-potassium chloride cotransporter (NKCC), respectively. This study meets Xavier University's institutional goal to eliminate health disparity. This pilot study will contribute significantly to knowledge and provide further insights into the molecular and cellular underpinnings of impaired sodium handling in diabetes. The information obtained from this study will enable the Principal Investigator to apply for competitive external grants like R01 in the future. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a life-long disease characterized by high levels of sugar in the blood and accounts for 90-95% of people diagnosed with diabetes. Over time, it can lead to dehydration, hypertension, renal disease, and artherosclerosis. Pioglitazone is an antidiabetic agent used in the treatment of type 2 diabetes. This pilot study will define a role for pioglitazone in sodium handling in type 2 diabetes in db/db mice.

描述（由申请人提供）：来自世界卫生组织的估计表明，世界上有大约1.3亿个被诊断的糖尿病患者，该数字预计到2025年将增加到3亿。神经性问题（Oki等，2002）。 2型糖尿病与许多心血管风险有关，包括血脂异常和高血压。它是终末期肾脏疾病（ESDR）的主要原因，它表现为肾脏处理钠的能力的干扰。已经引入了噻唑烷二酮（TZD），用于治疗2型糖尿病。这些药物是过氧化物酶体增殖物激活的伽马受体（PPAR3）的配体，并且用于2型糖尿病中，因为它们通过降低葡萄糖来通过降低胰岛素耐药性来降低葡萄糖水平。在我们先前的研究中，我们定义了PPAR1在肾脏钠处理中的作用，结果表明，PPAR1基因的缺失导致Na-CL共转运蛋白（NCC）活性有缺陷，这是通过降低的氢氯噻嗪敏感性钠的排泄物所证明的。基于这些观察结果，我们假设在2型糖尿病中钠处理受损，并且PPAR1基因提供了免受钠损伤的保护。由于PPAR3和PPAR1具有相同的过氧化物酶体响应元件，并且可以通过相同的配体进行反式激活，因此我们假设PPAR3将在2型糖尿病中的钠处理中起定义的作用。为了实现这一目标，我们将使用DB/DB小鼠和PPAR配体，Pioglitazone来剖析PPAR3在2型糖尿病中的钠处理中的参与。在第一组实验中，糖尿病，db/db - / - 小鼠将在饮食中的钠负荷挑战，并评估钠排泄的程度。 In another set of experiments, we will examine the role of pioglitazone in in vivo natriuretic mechanisms in type 2 diabetes by evaluating the differential sensitivity of ion transporters in the nephron to hydrochlorothiazide, amiloride, or furosemide, as indices of activity of sodium chloride co-transporter (NCC), sodium hydrogen exchanger （NHE）和氯化钠共转运蛋白（NKCC）。这项研究符合Xavier大学消除健康差异的机构目标。这项试验研究将对知识产生重大贡献，并为糖尿病中钠处理受损的分子和细胞基础提供进一步的见解。从这项研究中获得的信息将使主要研究人员能够将来申请竞争性的外部赠款。 公共卫生相关性：2型糖尿病是一种终身疾病，其特征是血液中高水平的糖，占诊断患有糖尿病的人的90-95％。随着时间的流逝，它可能导致脱水，高血压，肾脏疾病和眼前疾病。吡格列酮是一种用于治疗2型糖尿病的抗糖尿病药物。这项试验研究将定义吡格列酮在DB/DB小鼠2型糖尿病中的钠处理中的作用。