Molecular Mechanisms of Distal Sodium Transport in Insulin Resistance

胰岛素抵抗中远端钠转运的分子机制

• 批准号: 7788773
• 负责人: VIVEK BHALLA
• 金额: $ 8.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788773
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Award; Binding; Biochemistry; Blood; Blood Pressure; Carbohydrates; Cardiovascular Diseases; Cell Culture System; Cells; Chronic; Collecting Cell; Compensatory Hyperinsulinemia; Data; Diet; Distal; Diuretics; Dose; Duct (organ) structure; Epidemiologic Studies; Epithelial; Essential Hypertension; Fatty acid glycerol esters; Fructose; Functional disorder; Funding; General Population; Generations; Genetic Models; Glucocorticoids; Grant; Hormones; Hyperinsulinism; Hypertension; In Vitro; Incidence; Individual; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Kidney; Learning; Link; Manuscripts; Measures; Mediating; Mediator of activation protein; Mentors; Molecular; Mus; Nephrons; Pathway interactions; Patients; Peripheral; Phosphotransferases; Play; Primary Cell Cultures; Principal Investigator; RNA Interference; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Relative (related person); Research; Resources; Rodent Model; Role; Second Messenger Systems; Serum; Signal Transduction; Sodium; Sodium Channel; Sodium Chloride; Syndrome; Techniques; Testing; Time; TimeLine; Tissues; Transgenic Mice; Tubular formation; United States National Institutes of Health; Writing; cardiovascular disorder risk; design; dosage; glucose disposal; in vivo; insulin sensitivity; kidney cell; leptin receptor; lipid metabolism; mouse model; new therapeutic target; programs; research study; salt sensitive; trafficking

DESCRIPTION (provided by applicant): Insulin resistance affects more than 50% of all hypertensive subjects and worsens their risk for cardiovascular disease. This syndrome is characterized by salt-sensitive hypertension due to increased sodium reabsorption in the distal nephron of the kidney. Currently there is no targeted therapy for this group of patients. Diuretics would counteract the natriferric effects of insulin resistance, but these agents adversely affect carbohydrate and lipid metabolism which may mitigate their benefit for hypertension. Discerning the molecular mechanisms which cause hypertension would highlight novel therapeutic targets for this syndrome. Several causes of this elevated blood pressure include compensatory hyperinsulinemia which may increase sodium transport despite peripheral insulin resistance, insulin-like growth factor-1 (IGF-1), which has also been demonstrated to increase sodium reabsorption in vivo, or perhaps altered intracellular signaling intermediates independent of insulin or IGF-1. Recent evidence suggests that the epithelial sodium channel (ENaC) which resides in the collecting duct may be responsible for enhanced distal sodium transport in insulin resistance. The Small Grant Award (NIH R03) will provide to the principal investigator (PI) the necessary resources to directly test the hypotheses that insulin resistance-associated hypertension is due to increased ENaC activity due to: (1) hyperinsulinemia, (2) IGF-1, or (3) altered post-insulin or post-IGF-1 receptor signaling within the distal nephron. The PI will isolate collecting duct (CD) cells from insulin-resistant vs. control mice and investigate the dose and time-dependent effects of insulin, IGF-1, or vehicle on receptor activation. Additionally, the PI will apply standard biochemistry and RNA interference techniques to elucidate the molecular pathways which regulate sodium transport in insulin, IGF-1, or vehicle-treated primary culture cells. Using two dietary and one genetic model of insulin resistance, will allow for broader, more clinically applicable conclusions to the data. The PI previously spent three years on the K08 studying the regulation of ENaC trafficking and for the final two years of the award will pursue related questions on sodium transport in pathophysiology. The proposed experiments are feasible and will lay the groundwork for generation of an independent R01-funded research program distinct from the primary mentor. PROJECT NARRATIVE As the incidence of insulin resistance increases in the general population, so will the incidence of hypertension and cardiovascular disease. By comparing sodium transport in kidney cells from mice with and without insulin resistance, we can learn more about how insulin resistance causes salt-sensitive hypertension and how to design specific therapies for this subset of individuals.

描述（由申请人提供）：胰岛素抵抗影响超过50%的高血压受试者，并增加他们患心血管疾病的风险。这种综合征的特征是由于肾脏远端肾单位钠重吸收增加而引起的盐敏感性高血压。目前还没有针对这类患者的靶向治疗。利尿剂会抵消胰岛素抵抗的钠铁效应，但这些药物会对碳水化合物和脂质代谢产生不利影响，这可能会降低其对高血压的益处。识别引起高血压的分子机制将突出这种综合征的新的治疗靶点。这种血压升高的几个原因包括代偿性高胰岛素血症，其可能增加钠转运，尽管外周胰岛素抵抗，胰岛素样生长因子-1（IGF-1），其也已被证明增加体内钠重吸收，或可能改变不依赖于胰岛素或IGF-1的细胞内信号传导中间体。最近的证据表明，位于集合管的上皮钠通道（ENaC）可能是胰岛素抵抗时远端钠转运增强的原因。小额资助奖（NIH R 03）将为主要研究者（PI）提供必要的资源，以直接检验胰岛素抵抗相关高血压是由于ENaC活性增加所致的假设：（1）高胰岛素血症，（2）IGF-1，或（3）远端肾单位内胰岛素后或IGF-1后受体信号传导改变。PI将从胰岛素抵抗小鼠与对照小鼠中分离收集管（CD）细胞，并研究胰岛素、IGF-1或溶剂对受体活化的剂量和时间依赖性影响。此外，PI将应用标准生物化学和RNA干扰技术阐明调节胰岛素、IGF-1或溶剂处理的原代培养细胞中钠转运的分子途径。使用两种饮食和一种胰岛素抵抗的遗传模型，将允许对数据得出更广泛，更临床适用的结论。PI之前在K 08上花了三年时间研究ENaC运输的调节，并在该奖项的最后两年将继续研究病理生理学中钠转运的相关问题。拟议的实验是可行的，并将为产生独立于主要导师的R 01资助的研究项目奠定基础。 项目叙述 随着一般人群中胰岛素抵抗发生率的增加，高血压和心血管疾病的发生率也会增加。通过比较有和没有胰岛素抵抗的小鼠肾细胞中的钠转运，我们可以更多地了解胰岛素抵抗如何导致盐敏感性高血压，以及如何为这部分人设计特定的治疗方法。