RENAL DOPAMINE RECEPTOR FUNCTION IN OBESE ZUCKER RATS

肥胖 Zucker 大鼠肾多巴胺受体功能

• 批准号: 6517840
• 负责人: Mustafa F. Lokhandwala
• 金额: $ 21.02万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517840
• 关键词: diuresis; dopamine; dopamine agonists; dopamine receptor; genetic strain; hyperinsulinism; laboratory rat; obesity; phosphorylation; protein structure function; receptor binding; renal tubular transport; saluresis

DESCRIPTION (Verbatim from the application): Dopamine and D1-like receptors in the proximal tubules and other regions of the nephron play an important role in regulating renal sodium excretion. A defective DIA receptor (a D1-like receptor) function is reported in the proximal tubules of hepertensive animals and humans. In our preliminary studies we found that D1-Iike receptors are reduced by 50 percent and dopamine was unable to stimulate second messengers (cAMP and IP3) and thereby failed to inhibit Na,K-ATPase and Na,H-exchanger in the proximal tubules of obese Zucker rats (12 week old). Therefore, it is hypothesized that the diminished inhibitory effect of dopamine on sodium transporting proteins in the proximal tubules is due to a dysfunction in DIA receptor which results from altered phosphorylation of membranal DIA receptor as well as impaired recruitment of newer D1A receptors from cytosol. Such a defect in dopamine receptor function contributes to the diminished natriuretic response to exogenously administered as well as endogenously produced dopamine. This hypothesis will be tested by conducting a series of experiments to identify the biochemical/molecular mechanism(s) contributing towards the defect in DIA receptors. These will include: measurement of D1A receptor agonist affinity, determination of the effect of GTPyS on ligand binding, determination of agonist-dependent and -independent phosphorylation of D1A receptor, determination of agonist recmitment of D1A receptors on the membrane and measurement of D1A receptor mRNA and DIA receptor protein content in proximal tubules of lean and obese rats. The functional consequence of the defective DIA receptor function will be examined by studying the natriuretic and diuretic effect of dopamine and SKF38393 as well as by determining the effect of acute volume expansion on renal production of dopamine and sodium and water excretion in anesthetized lean and obese Zucker rats. In order to delineate the role of hyperinsulinemia in causing the defective D1A receptor function and the natriuretic response, experiments described above will also be performed in lean and obese rats (7-8 weeks) treated for four weeks with darglitazone, a drug which decreases insulin levels and improve insulin sensitivity as well as in 3-4 week old non-treated hyperinsulinemic and control rats. Identification of the mechanism(s) leading to dopamine receptor dysfunction and the diminished natriuretic response to dopamine would allow us to better understand the relationship between kidney D1A receptor function and hyperinsulinemia in obese rats.

描述（来自申请的逐字）：多巴胺和D1样受体， 肾单位的近端小管和其它区域在 调节肾钠排泄。缺陷性DIA受体（D1样 受体）功能的报道，在近端小管的高血压动物 还有人类在我们的初步研究中，我们发现D1样受体 减少了50%，多巴胺无法刺激第二信使， (cAMP和IP 3），从而未能抑制Na，K-ATP酶和Na，H-交换， 肥胖Zucker大鼠（12周龄）的近端小管。 因此，可以假设多巴胺的抑制作用减弱 对近端小管中钠转运蛋白的影响是由于 在DIA受体中，其由膜DIA的磷酸化改变引起 受体以及受损的招聘较新的D1 A受体从胞质溶胶。 多巴胺受体功能的这种缺陷有助于减少 对外源性和内源性给药的利钠反应 产生多巴胺。这一假设将通过进行一系列 实验以确定生物化学/分子机制， 针对DIA受体的缺陷。这些将包括：D1 A的测量 受体激动剂亲和力，测定GTP γ S对配体的作用 结合，激动剂依赖性和非依赖性磷酸化的测定 D1 A受体，D1 A受体激动剂的测定 膜和D1 A受体mRNA和DIA受体蛋白含量的测量 在瘦和肥胖大鼠的近端小管中。的功能后果 DIA受体功能缺陷将通过研究尿钠排泄来检查。 多巴胺和SKF 38393的利尿作用以及通过测定 急性扩容对肾脏多巴胺和钠产生影响 在麻醉的瘦和肥胖Zucker大鼠中的水排泄。为了 描述高胰岛素血症在导致D1 A受体缺陷中的作用 功能和利钠反应，上述实验也将 在瘦和肥胖大鼠（7-8周）中进行，用 达格列酮，一种降低胰岛素水平和改善胰岛素分泌的药物， 敏感性以及3-4周龄未治疗高胰岛素血症和对照 大鼠确定导致多巴胺受体的机制 功能障碍和对多巴胺的利钠反应减弱 为了更好地了解肾脏D1 A受体功能与 高胰岛素血症。