Renal Angiotensin II Receptor Function in Obesity

肾血管紧张素 II 受体在肥胖中的功能

• 批准号: 8549192
• 负责人: TAHIR HUSSAIN
• 金额: $ 30.86万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-15 至 2016-05-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549192
• 关键词: AGTR2 gene; Aftercare; Agonist; Angiotensin II; Angiotensin II Receptor; Animal Model; Animals; Biochemical; Blood Glucose; Blood Pressure; Cardiovascular Physiology; Cell Culture Techniques; Cell membrane; Cells; Cyclic GMP; Development; Diabetes Mellitus; Equilibrium; Excretory function; Figs - dietary; Fluorescein-5-isothiocyanate; Funding; Glomerular Filtration Rate; Glucose; Goals; Guanylate Cyclase; HK2 gene; Health; Hyperglycemia; Hypertension; Hypotension; IRF1 gene; Insulin; Insulin Resistance; Inulin; Kidney; Long-Term Effects; MAPK14 gene; Measures; Mediating; Messenger RNA; Methodology; Methods; Modeling; Molecular Biology; Na(+)-K(+)-Exchanging ATPase; Natriuresis; Nitric Oxide; Obesity; Pathway interactions; Physiological; Plasma; Proteins; Proximal Kidney Tubules; Rattus; Receptor Activation; Regulation; Renal function; Renin; Renin-Angiotensin System; Reporting; Role; Sodium; Telemetry; Testing; Therapeutic; Transcriptional Activation; Transcriptional Regulation; United States; Zucker Rats; analog; base; blood pressure regulation; diabetic; diabetic rat; fluorescence imaging; improved; inhibitor/antagonist; knock-down; mRNA Expression; mitogen-activated protein kinase p38; novel; phosphoric diester hydrolase; public health relevance; receptor; receptor expression; receptor function; response; rosiglitazone; therapeutic target; transcription factor; urinary

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to evaluate a physiological and therapeutic role for the renal angiotensin II (Ang II) AT2 receptors in improving renal/cardiovascular function and treating hypertension associated with obesity/diabetes. Of the two Ang II receptors, AT1 is known to mediate most of the Ang II actions such as antinatriuresis and increased blood pressure (BP). The AT2 receptor is suggested to function as an antagonist of AT1 receptors; however, low expression of the AT2 receptor has hindered development of a clear understanding of the physiological and therapeutic roles of this receptor. During the previous funding period, we found that hyperglycemia, associated with either insulin resistance or insulin insufficiency, caused an increase in AT2 receptor expression in the renal proximal tubule. Selective activation of the AT2 receptors stimulated a nitric oxide/cGMP pathway, thus inhibiting proximal tubule Na,K-ATPase (NKA) activity and increasing urinary Na excretion in obese Zucker rats, a model of insulin resistance and hyperglycemia. Treatment of obese rats with an AT2 receptor antagonist for 2 weeks raised BP in these animals. Three hypotheses were developed from these observations. First, hyperglycemia increases AT2 receptor expression by transcriptional activation. Second, selective AT2 receptor activation directly inhibits NKA via a NO/cGMP pathway and also, antagonizes the AT1 receptor-mediated NKA stimulation in proximal tubules by cGMP- mediated inhibition of phosphodiesterase-3 (PDE-3). Third, long-term selective AT2 receptor activation increases urinary Na excretion and lowers BP in obese Zucker/diabetic rats. These hypotheses will be tested by 3 specific aims utilizing cell culture and whole animal models. Aim 1 will study the role of p38 MAP kinase and transcription factors IRF-1 and C/EBP2 in increasing AT2 receptor expression by high glucose concentrations in HK-2 cells; renal AT2 receptor expression/function in obese rats with euglycemia. Aim 2 will study the role of cGMP-mediated PDE-3 inhibition, as a novel mechanism responsible for AT2 receptor antagonism of AT1 receptor-stimulated NKA, in isolated proximal tubules of obese Zucker rats. In aim 3, we will study the effect of long-term treatment with an AT2 agonist on renal function and BP in control in kidney- specific AT2 knock-down obese/lean Zucker rats. Following treatments, proximal tubule NKA activity and various components of the renin angiotensin system will be determined. Biochemical, immunological, molecular biology, fluorescence imaging and whole animal physiological methodologies will be employed to accomplish the proposed studies. These studies will elucidate the mechanisms regulating AT2 receptor in diabetes. Moreover, they will advance our understanding of the physiological role of the AT2 receptor in the long-term regulation of renal function and blood pressure control. Finally, the studies may clarify the potential of the AT2 receptor as an important therapeutic target providing a strong basis to develop selective non-peptide AT2 agonists.

描述（由申请人提供）：该提案的长期目标是评估肾血管紧张素II（ANG II）AT2受体在改善肾脏/心血管功能方面的生理和治疗作用，并治疗与肥胖/糖尿病相关的高血压。在两个ANG II受体中，众所周知，AT1介导了大多数ANG II作用，例如抗亚钠和血压升高（BP）。建议AT2受体充当AT1受体的拮抗剂。然而，AT2受体的低表达阻碍了对该受体的生理和治疗作用的清晰理解。在上一个资金期间，我们发现与胰岛素抵抗或胰岛素不足有关的高血糖导致肾近端小管中AT2受体表达的增加。 AT2受体的选择性激活刺激了一氧化氧化物/CGMP途径，因此抑制了近端小管Na，K-ATPase（NKA）活性，并增加了肥胖的Zucker大鼠的尿Na排泄，这是一种胰岛素抵抗和高血糖症的模型。用AT2受体拮抗剂治疗肥胖大鼠在这些动物中升高了2周。从这些观察结果提出了三个假设。首先，高血糖通过转录激活增加了AT2受体表达。其次，选择性AT2受体激活通过NO/CGMP途径直接抑制NKA，并且还通过CGMP介导的磷酸二酯酶-3（PDE-3）抑制近端小管中AT1受体介导的NKA刺激（PDE-3）。第三，长期选择性AT2受体激活会增加肥胖的Zucker/糖尿病大鼠的尿NA排泄，并降低BP。这些假设将通过使用细胞培养和整个动物模型的3个特定目的来检验。 AIM 1将研究p38 MAP激酶和转录因子IRF-1和C/EBP2在HK-2细胞中高葡萄糖浓度增加AT2受体表达中的作用；肥胖大鼠的肾脏AT2受体表达/功能。 AIM 2将研究CGMP介导的PDE-3抑制作用的作用，这是负责AT1受体刺激的NKA AT2受体拮抗的新机制，在肥胖的Zucker大鼠的分离近端小管中。在AIM 3中，我们将研究AT2激动剂对肾功能和BP在肾脏特异性AT2敲击肥胖/瘦扎克大鼠中对照中的长期治疗的影响。在处理后，将确定近端小管NKA活性和肾素血管紧张素系统的各种成分。将采用生化，免疫学，分子生物学，荧光成像和整个动物生理方法来完成所提出的研究。这些研究将阐明调节糖尿病中AT2受体的机制。此外，他们将促进我们对AT2受体在肾功能和血压控制的长期调节中的生理作用的理解。最后，研究可能会阐明AT2受体作为重要的治疗靶标的潜力，从而为开发选择性非肽AT2激动剂提供了强大的基础。