Prorenin Receptors Mediate Hypertension and Kidney Disease in Diabetes

肾素原受体介导糖尿病中的高血压和肾脏疾病

• 批准号: 7745451
• 负责人: Helmy M Siragy
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7745451
• 关键词: Adult; Aldosterone; Angiotensin II; Angiotensins; Blood Vessels; CCL2 gene; Cardiovascular Diseases; Complement Factor B; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Endothelin-1; Funding; Glucose; Hyperglycemia; Hypertension; Individual; Inflammation; Inflammatory; Interleukin-1 alpha; Kidney; Kidney Diseases; Kidney Glomerulus; Lead; MAP Kinase Gene; Mediating; Modality; Morbidity - disease rate; Names; Nuclear; Organ; Pathologic; Phosphorylation; Physiological; Principal Investigator; Production; Protein Kinase C; Proteinuria; Rattus; Renal Glycosuria; Renin-Angiotensin System; Research; Staging; Structure; Testing; Transforming Growth Factors; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; inhibitor/antagonist; mortality; novel; novel therapeutics; prevent; programs; prorenin receptor; receptor; receptor expression

DESCRIPTION (provided by applicant): The association of hypertension and kidney disease in diabetes is common and is associated with increased morbidity and mortality. Although inhibitors of the renin angiotensin system (RAS) are being used to treat hypertension and diabetic kidney disease, the number of individuals the mortality rate from cardiovascular disease continues to be high. All components of the RAS are present in the kidney in close proximity to the involved renal structures. Angiotensin II (Ang II) subtype-1 (AT1) receptors are localized in the renal blood vessels, glomeruli and tubules. Ang II subtype-2 (AT2) receptors are detected in adult rat kidney glomeruli, blood vessels and tubules. In the previous funding period of this application we demonstrated that there is a decrease in AT2 receptor expression and activity in presence of diabetes which contributes to development of renal disease through increased renal production of inflammatory and other vaso-active factors such as tumor necrosis factor-a (TNFa), transforming growth factor-¿1 (TGF¿1), endothelin-1 (ET- 1), thromboxan-¿2 and local renal production of aldosterone. Recently, a novel prorenin receptor (MW 39KD) was discovered and localized in multiple organs including the kidney. The physiologic and pathologic functions of the prorenin receptors are unknown; much less it is interaction with the other components of the RAS. Our preliminary studies suggest that high glucose upregulates this receptor expression in the kidney leading to increased renal production of inflammatory factors. Independent of Ang II, it increases renal production of nuclear factor-?B, TNFa and interlukin-6 (IL-6). In addition we have preliminary data demonstrating presence of another novel form of the prorenin receptor (MW 66KD) which seems to have a major contribution to development of hypertension and kidney disease in presence of diabetes. This proposal will evaluate the hypothesis that in presence of diabetes, renal prorenin receptors mediate renal inflammation and matrix formation which contributes to development of hypertension and kidney disease. The proposed specific aims are: AIM I: To test the hypothesis that glucose upregulates prorenin receptors expression through stimulation of protein kinase C -MAPK- cJun cascade. AIM II: To test the hypothesis that in presence of hyperglycemia the cellular effects of the prorenin receptors are mediated via stimulation of ERK phosphorylation, NF?B, TNFa, IL-1, IL-6 and MCP-1, and is modulated by the interaction with the angiotensin AT1 and AT2 receptors. AIM III: To test the hypothesis that in early stage diabetic nephropathy, prorenin receptor contributes to development of renal inflammation, matrix formation, proteinuria and hypertension. The proposed studies will help elucidate the mechanisms that are involved in development of hypertension and kidney disease and could lead to the development of new therapeutic modalities to prevent or slowdown the development of these diseases.

描述（由申请人提供）：糖尿病中高血压和肾脏疾病的相关性很常见，并与发病率和死亡率增加相关。尽管肾素血管紧张素系统（RAS）的抑制剂被用于治疗高血压和糖尿病肾病，但心血管疾病的死亡率仍然很高。RAS的所有组分都存在于肾脏中，紧邻受累的肾脏结构。血管紧张素II（AngII）亚型-1（AT 1）受体定位于肾血管、肾小球和肾小管中。在成年大鼠肾小球、血管和肾小管中检测到血管紧张素II亚型-2（AT 2）受体。在本申请的前一个资助期，我们证明了在糖尿病存在时AT 2受体表达和活性降低，这通过增加肾脏产生炎症和其他血管活性因子如肿瘤坏死因子-α（TNF α）、转化生长因子-α 1（TGF β 1）、内皮素-1（ET- 1）、血栓素-1（TXB 2）来促进肾脏疾病的发展。2和肾局部醛固酮的产生。最近发现了一种新的肾素原受体（分子量为39 KD），并定位于包括肾脏在内的多个器官。前肾素受体的生理和病理功能尚不清楚，更不用说它与RAS的其他组分的相互作用了。我们的初步研究表明，高葡萄糖上调这种受体在肾脏中的表达，导致肾脏炎症因子的产生增加。独立的血管紧张素II，它增加肾生产的核因子-？B、TNF α和白细胞介素-6（IL-6）。此外，我们有初步数据表明存在另一种新形式的前肾素受体（MW 66 KD），这似乎对糖尿病患者的高血压和肾脏疾病的发展有重大贡献。本提案将评估在糖尿病存在下，肾前肾素受体介导肾脏炎症和基质形成的假设，这有助于高血压和肾脏疾病的发展。目的：1.验证葡萄糖通过刺激蛋白激酶C-MAPK- cJun级联反应上调肾素原受体表达的假说。AIM II：为了检验假设，在存在高血糖的情况下，通过刺激ERK磷酸化，NF？B、TNF α、IL-1、IL-6和MCP-1，并且通过与血管紧张素AT 1和AT 2受体的相互作用来调节。AIM III：为了验证在早期糖尿病肾病中，前肾素受体参与肾脏炎症、基质形成、蛋白尿和高血压的发展的假设。拟议的研究将有助于阐明参与高血压和肾脏疾病发展的机制，并可能导致新的治疗方式的发展，以预防或减缓这些疾病的发展。