Transcriptional Regulation of Natriuetic Sensitivity in Diabetes Mellitus

糖尿病钠敏感性的转录调控

• 批准号: 8318586
• 负责人: Patience O Obih
• 金额: $ 15.48万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318586
• 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.

描述（由申请人提供）：世界卫生组织的估计表明，世界上约有1.3亿确诊的糖尿病患者，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相关，导致慢性并发症，包括微血管、大血管和神经性问题（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。它是终末期肾病（ESDR）的主要原因，表现为肾脏处理钠的能力紊乱。噻唑烷二酮类（TZD）已被引入用于治疗2型糖尿病。这些药物是过氧化物酶体增殖物激活的γ受体（PPAR 3）的配体，并且用于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。在我们以前的研究中，我们确定了PPAR 1在肾脏钠处理中的作用，我们的结果表明，PPAR 1基因的缺失导致了缺陷的钠-氯协同转运蛋白（NCC）活性，这一点可以通过减少氢氯噻嗪敏感性钠排泄来证明。基于这些观察结果，我们假设2型糖尿病患者的钠处理功能受损，而PPAR 1基因提供了对钠损伤的保护。由于PPAR 3和PPAR 1共享相同的过氧化物酶体反应元件，并且可以被相同的配体反式激活，因此我们假设PPAR 3将在2型糖尿病的钠处理中发挥确定的作用。为了实现这一目标，我们将使用db/db小鼠和PPAR配体吡格列酮来分析PPAR 3在2型糖尿病钠处理中的参与。在第一组实验中，糖尿病db/db -/-小鼠将用饮食中的钠负荷进行激发，并评价钠排泄的程度。在另一组实验中，我们将通过评价肾单位中离子转运蛋白对氢氯噻嗪、阿米洛利或呋塞米的不同敏感性，分别作为氯化钠协同转运蛋白（NCC）、钠氢交换蛋白（NHE）和钠-氯化钾协同转运蛋白（NKCC）活性的指标，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机构目标。这项试点研究将有助于显着的知识，并提供进一步的见解受损的钠处理糖尿病的分子和细胞基础。从本研究中获得的信息将使主要研究者能够在未来申请像R 01这样的竞争性外部赠款。