Prorenin Receptors Mediate Hypertension and Kidney Disease in Diabetes

描述（由申请人提供）：糖尿病患者高血压和肾脏疾病的关联是常见的，并且与发病率和死亡率增加有关。尽管肾素血管紧张素系统（RAS）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的所有成分都存在于肾脏中，靠近受累的肾脏结构。血管紧张素II （Ang II）亚型-1 （AT1）受体定位于肾血管、肾小球和小管。在成年大鼠肾小球、血管和小管中检测到Ang II亚型-2 （AT2）受体。在本应用的前期资助期内，我们证明糖尿病患者的AT2受体表达和活性降低，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-a （TNFa）、转化生长因子-1 （TGF -1）、内皮素-1 （ET- 1）、血栓素- 2和局部肾生成醛固酮，从而促进肾脏疾病的发展。最近，一种新的催乳素受体（MW 39KD）被发现并定位于包括肾脏在内的多个器官。催乳素受体的生理和病理功能尚不清楚；更不用说与RAS的其他组件的交互了。我们的初步研究表明，高葡萄糖上调该受体在肾脏中的表达，导致肾脏炎症因子的产生增加。独立于angii，它增加肾核因子-？B、TNFa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催乳素受体（MW 66KD），它似乎对糖尿病患者的高血压和肾脏疾病的发展有重要贡献。本研究将评估在糖尿病存在的情况下，肾泌素受体介导肾脏炎症和基质形成，从而导致高血压和肾脏疾病的发生。提出的具体目的是：目的1：验证葡萄糖通过刺激蛋白激酶C - mapk - cJun级联上调prorenin受体表达的假设。目的II：验证假设，在高血糖的情况下，催乳素受体的细胞效应是通过刺激ERK磷酸化介导的，NF？B, TNFa, IL-1， IL-6和MCP-1，并通过与血管紧张素AT1和AT2受体的相互作用进行调节。目的III：验证早期糖尿病肾病中prorenin受体参与肾脏炎症、基质形成、蛋白尿和高血压的假设。提出的研究将有助于阐明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。

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.