RENAL DOPAMINE RECEPTOR FUNCTION IN OBESE ZUCKER RATS

肥胖 Zucker 大鼠肾多巴胺受体功能

• 批准号: 6707999
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6707999
• 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（来自应用程序）：多巴胺和d1样受体

项目成果

Dopamine recruits D1A receptors to Na-K-ATPase-rich caveolar plasma membranes in rat renal proximal tubules.

多巴胺将 D1A 受体募集到大鼠肾近曲小管中富含 Na-K-ATP 酶的细胞膜穴质膜上。

• DOI: 10.1152/ajprenal.00023.2004
• 发表时间: 2004
• 期刊: American journal of physiology. Renal physiology
• 作者: Trivedi,Meghna;Narkar,VihangA;Hussain,Tahir;Lokhandwala,MustafaF
• 通讯作者: Lokhandwala,MustafaF

Dopamine fails to inhibit Na,H-exchanger in proximal tubules of obese Zucker rats.

多巴胺不能抑制肥胖 Zucker 大鼠近端肾小管中的 Na,H 交换器。

• DOI: 10.1081/ceh-100107389
• 发表时间: 2001
• 期刊: Clinical and experimental hypertension (New York, N.Y. : 1993)
• 作者: Hussain,T;Becker,M;Beheray,S;Lokhandwala,MF
• 通讯作者: Lokhandwala,MF