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）：世界卫生组织的估计表明，世界上约有1.3亿确诊糖尿病患者，预计到2025年这一数字将增加到3亿。糖尿病是一种以高血糖为特征的代谢性疾病，与碳水化合物、脂肪和蛋白质代谢异常有关，可导致微血管、大血管和神经病变等慢性并发症（Oki et al, 2002）。2型糖尿病与许多心血管风险相关，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，其表现为肾脏处理钠的能力紊乱。噻唑烷二酮类药物（TZDs）已被用于治疗2型糖尿病。这些药物是过氧化物酶体增殖体激活γ受体（PPAR3）的配体，用于2型糖尿病，因为它们通过降低胰岛素抵抗来降低葡萄糖水平。在我们之前的研究中，我们确定了PPAR1在肾脏处理钠中的作用，我们的结果表明，PPAR1基因的缺失导致Na-Cl共转运体（NCC）活性缺陷，氢氯噻嗪敏感钠排泄减少证明了这一点。基于这些观察，我们假设2型糖尿病患者对钠的处理受损，而PPAR1基因提供了对钠损伤的保护。由于PPAR3和PPAR1具有相同的过氧化物酶体反应元件，并且可以被相同的配体反激活，因此我们假设，PPAR3将在2型糖尿病的钠处理中发挥明确的作用。为了实现这一目标，我们将使用db/db小鼠和PPAR配体、吡格列酮来解剖PPAR3在2型糖尿病钠处理中的作用。在第一组实验中，对糖尿病小鼠，db/db -/-小鼠进行钠负荷刺激，并评估其钠排泄程度。在另一组实验中，我们将通过评估肾单位中离子转运体对氢氯噻嗪、阿米洛利或速尿的不同敏感性，分别作为氯化钠共转运体（NCC）、钠氢交换剂（NHE）和氯化钠-钾共转运体（NKCC）活性的指标，来研究吡格列酮在2型糖尿病体内利钠机制中的作用。这项研究符合泽维尔大学消除健康差距的制度目标。这项初步研究将对糖尿病患者钠处理受损的分子和细胞基础有重大贡献，并提供进一步的见解。从这项研究中获得的信息将使首席研究员能够在未来申请有竞争力的外部资助，如R01。