Pathophysiological role of prorenin in CKD

肾素原在 CKD 中的病理生理作用

• 批准号: 8908007
• 负责人: Alfred K Cheung
• 金额: $ 37.93万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-27 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908007
• 关键词: Albuminuria; Aldosterone; Angiotensin I; Angiotensin II; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animals; Archives; Binding; Biological; Biological Assay; Biology; Blood; Caliber; Cardiac; Cardiac Myocytes; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Clinical Research; Cohort Studies; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Echocardiography; Enrollment; Etiology; Event; Eye; Eye diseases; Feedback; Generations; Goals; Health; Heart; Heart Diseases; Heart failure; Immunoassay; Inactive Renin; Incentives; Intracellular Signaling Proteins; Kidney; Kidney Diseases; Laboratories; Left; Measures; Mediating; Microvascular Dysfunction; Mission; National Institute of Diabetes and Digestive and Kidney Diseases; Observational Study; Organ; Outcome; Outcome Study; Parents; Participant; Pathway interactions; Patients; Pharmacotherapy; Population; Process; Production; Renin; Renin-Angiotensin-Aldosterone System; Retinal; Retinal Diseases; Role; Sampling; Serum; Severities; System; Testing; Variant; cohort; diabetic; follow-up; inhibitor/antagonist; insight; mesangial cell; non-diabetic; novel; receptor; receptor binding; retina blood vessel structure; success; time interval

DESCRIPTION (provided by applicant): Angiotensin (Ang) II are known to mediate the progression of chronic kidney disease (CKD) and cardiac disease. Hence, angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) have been used extensively to treat these clinical disorders. However, these agents often do not halt the disease processes. A potential reason for this limitation in success is the increase in prorenin and renin production, as a result of positive feedback. Renin and its precursor prorenin are biological active molecules, independent of the proteolytic action of renin that leads to the subsequent generation of Ang II. This Ang-independent pathway is initiated by the binding of either prorenin or renin to the (pro)renin receptor, that is present in the kidney, heart and eye. This receptor binding leads to the activation of intracellular signaling proteins that results in pro-proliferatie and pro-fibrotic cellular events that are not blocked by clinically used ACEI, ARB or direct renin inhibitors. Several small clinical studies have found a correlation between serum prorenin/renin levels with the development of microvascular diseases, including albuminuria and retinopathy, in patients with diabetes. Animal studies also found that activation of the (pro)renin receptor induces cardiac diseases. The over-arching hypothesis of the present proposal is that binding of prorenin and renin to the cellular (pro)renin receptor causes organ damage in an Ang-independent manner. Therefore, high serum levels of prorenin and/or renin are associated with CKD progression as well as the development or progression of heart failure and retinopathy. The NIDDK-sponsored Chronic Renal Insufficiency Cohort (CRIC) has enrolled 3,939 people with CKD in a longitudinal observational study. A variety of clinical and laboratory data as well as biospecimens have been collected during a 10-year follow-up period. This parent CRIC Study therefore provides an ideal setting to test our hypotheses. Prorenin and renin will be measured using highly specific immunoassays in archived serum samples collected annually from CRIC participants. Using these assay results, we propose to: (i) characterize the distribution of serum prorenin and renin levels and their longitudinal variations; (ii) determine te association of serum prorenin and renin levels with subsequent CKD progression; (iii) determine the association of serum prorenin and renin levels with subsequent changes in cardiac function on echocardiography and clinical cardiac events; and (iv) determine the cross-sectional association of serum prorenin and renin levels with retinopathy on fundoscopic examination. The proposed study will develop novel insights into the pathogenic roles of prorenin and renin. Importantly, positive results will provide strong rationales to develop new strategies to target th Ang II-independent effects of prorenin and renin for the treatment of nephropathy, retinopathy and cardiac failure. This project perfectly aligns with the mission of the NIDDK to study and develop treatments for people with CKD and diabetes.

描述（由申请人提供）：已知血管紧张素（Ang） II介导慢性肾脏疾病（CKD）和心脏病的进展。因此，血管紧张素转换酶抑制剂（ACEI）和血管紧张素受体阻滞剂（ARB）已被广泛用于治疗这些临床疾病。然而，这些药物往往不能阻止疾病的发展。这种成功限制的一个潜在原因是，由于积极的反馈，泌乳素和肾素的产生增加。肾素及其前体原肾素是生物活性分子，独立于肾素的蛋白水解作用，导致Ang II的后续产生。这种不依赖于ang的途径是由前肾素或肾素与存在于肾脏、心脏和眼睛中的（前）肾素受体结合而启动的。这种受体结合导致细胞内信号蛋白的激活，导致促增殖和促纤维化细胞事件，而这些事件不会被临床使用的ACEI、ARB或直接肾素抑制剂阻断。几项小型临床研究发现，糖尿病患者血清前肾素/肾素水平与微血管疾病（包括蛋白尿和视网膜病变）的发展之间存在相关性。动物研究也发现（原）肾素受体的激活会诱发心脏病。目前提出的首要假设是，prorenin和肾素结合到细胞（pro）肾素受体以一种不依赖于ang的方式引起器官损伤。因此，血清中prorenin和/或肾素的高水平与CKD的进展以及心力衰竭和视网膜病变的发生或进展有关。niddk赞助的慢性肾功能不全队列（CRIC）在一项纵向观察研究中招募了3939名CKD患者。在10年的随访期间收集了各种临床和实验室数据以及生物标本。因此，本研究为检验我们的假设提供了一个理想的环境。每年从CRIC参与者收集的存档血清样本中，将使用高度特异性的免疫测定法测量原肾素和肾素。利用这些检测结果，我们建议：(i)表征血清催肾素和肾素水平的分布及其纵向变化；（ii）测定血清前肾素和肾素水平与随后CKD进展的关系；（iii）确定血清前肾素和肾素水平与超声心动图和临床心脏事件的心功能变化之间的关系；（iv）确定眼底镜检查时血清prorenin和肾素水平与视网膜病变的横断面相关性。拟议的研究将对催乳素和肾素的致病作用产生新的见解。重要的是，积极的结果将为开发新的策略提供强有力的依据，以靶向prorentin和肾素治疗肾病、视网膜病变和心力衰竭的不依赖于angii的作用。该项目完全符合NIDDK的使命，即研究和开发CKD和糖尿病患者的治疗方法。