Protective Arm of the Renin Angiotensin System in Obese Kidney

肥胖肾脏中肾素血管紧张素系统的保护臂

• 批准号: 9899744
• 负责人: TAHIR HUSSAIN
• 金额: $ 40.35万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899744
• 关键词: AGTR2 gene; Acute; Acute Renal Failure with Renal Papillary Necrosis; Affect; Agonist; Albuminuria; Angiotensin II; Animal Model; Anti-Inflammatory Agents; Attenuated; Biochemical; Blood Urea Nitrogen; Cardiovascular Diseases; Cell physiology; Cells; Chronic; Coculture Techniques; Complex; Critical Pathways; Diabetes Mellitus; Encapsulated; Epithelial Cells; Equilibrium; Estrogens; Fatty acid glycerol esters; Female; Health; Histologic; Homeostasis; Human; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Injury to Kidney; Interleukin-10; Interleukin-6; Ischemia; Kidney; Knock-out; Macrophage Activation; Maintenance; Mediating; Microbubbles; Molecular; Mus; Natriuresis; Normal saline; Obesity; Outcome; Pathway interactions; Phase; Plasma; Play; Process; Proximal Kidney Tubules; Rattus; Receptor Activation; Recovery; Renal function; Renin-Angiotensin System; Reperfusion Injury; Reperfusion Therapy; Risk Factors; Role; Scheme; Series; Sex Bias; Sodium; Structure; TNF gene; Techniques; Technology; Testing; Tubular formation; Type 2 Angiotensin II Receptor; United States; Vacuole; Zucker Rats; arm; blood pressure regulation; cell type; combat; cytokine; drinking water; experimental study; improved; in vivo; indexing; kidney cell; kidney epithelial cell; kidney repair; knock-down; macrophage; mannose receptor; new therapeutic target; novel; plasmid DNA; prevent; receptor; renal damage; repaired; response; small hairpin RNA; tissue injury; tissue repair

Project Summary Obesity is a risk factor for chronic as well as acute kidney injury (AKI). Chronic kidney injury arises as a result of progressive loss of kidney function leading to irreversible damage, while AKI occurs as an abrupt loss of kidney function and usually is reversible. In both processes, inflammation plays an important role in the initiation and maintenance of the injury. Renal inflammation is influenced by an interplay of pro- and anti- inflammatory cytokines released by kidney cells and macrophages (broadly defined M1 and M2 types). While M1 type are pro-inflammatory and cause renal injury (chronic and acute), M2 are anti-inflammatory and help repair post AKI during the recovery phase. Thus altering the interplay between kidney cells and macrophages offers a potential novel target to combat local inflammation and protect the kidney from chronic as well acute injury. Recently, we and others have revealed that angiotensin type 2 receptors (AT2R) exert anti-inflammatory and reno-protective actions, novel functions of AT2R in addition to natriuresis and blood pressure regulation. Our preliminary studies in pre-hypertensive obese rat and mice suggest that AT2R agonist treatment reduces inflammatory cytokines and protects against chronic kidney injury as well as AKI. A series of in vitro experiments in human kidney proximal tubule epithelial cells (HK-2) and macrophages (THP-1 cells) revealed that AT2R activation increases IL-10, which may be critical pathway in reducing pro-inflammatory cytokines and creating a cross-talk between proximal tubules and macrophages, including shifting macrophages from M1 to M2 type. These studies provide a strong premise to hypothesize that AT2R activation promotes a cross-talk (interplay) between kidney epithelial cells and macrophages, via the anti-inflammatory IL-10 pathway, preventing chronic and acute kidney injury in obesity. Moreover, AT2R shifts the macrophage balance between M1 and M2 types limiting kidney injury and promoting repair, particularly in AKI in obesity. To test this hypothesis, Aim 1 is directed to determine that renal AT2R via IL-10 pathway reduces local inflammation and protects kidney against chronic injury in obesity. Aim 2 will study that AT2R activation attenuates AKI and promotes kidney repair via a macrophage polarity shift towards M2 type. Uninephrectomized obese Zucker rats will be used and placed on normal saline for chronic kidney injury and subjected to ischemia/reperfusion (I/R) for AKI. Kidney specific knockdown of AT2R and IL-10 will achieved by utilizing shRNA plasmid DNA encapsulated in microbubble technology, to study the role of kidney AT2R and IL-10 in reno-protection, anti- inflammation and kidney repair. To define AT2R gender bias, experiments to study the role of estrogen in AT2R-mediated reno-protection in females have been included. State-of-the-art techniques will be employed to determine biochemical, histological and molecular outcomes of kidney injury and function. The proposed studies will elucidate the novel role of the kidney AT2R in reno-protection and identify it as a novel therapeutic target for preventing and repairing kidney injury.

项目摘要 肥胖是慢性和急性肾脏损伤（AKI）的危险因素。结果出现了慢性肾脏损伤 肾脏功能的进行性丧失导致不可逆转的损害，而AKI的发生是突然丧失 肾功能，通常是可逆的。在这两个过程中，炎症在 受伤的启动和维护。肾脏炎症受促疾病和抗 - 肾细胞和巨噬细胞释放的炎性细胞因子（广泛定义的M1和M2类型）。尽管 M1类型是促炎性的，并引起肾脏损伤（慢性和急性），M2具有抗炎和帮助 在恢复阶段维修AKI。因此改变了肾细胞与巨噬细胞之间的相互作用 提供了一个潜在的新型目标，可以抵抗局部炎症并保护肾脏免受慢性和急性的侵害 受伤。最近，我们和其他人透露，血管紧张素2型受体（AT2R）发挥抗炎作用 以及肾脏保护作用，除纳地尿和血压调节外，AT2R的新功能。 我们在催眠前肥胖大鼠和小鼠中的初步研究表明AT2R激动剂治疗可降低 炎症性细胞因子并防止慢性肾脏损伤和AKI。一系列体外 人肾近端小管上皮细胞（HK-2）和巨噬细胞（THP-1细胞）的实验显示 AT2R激活增加了IL-10，这可能是减少促炎性细胞因子和 在近端小管和巨噬细胞之间建立串扰，包括将巨噬细胞从M1转移到 M2类型。这些研究提供了有力的前提，可以假设AT2R激活促进了跨对话 （相互作用）通过抗炎IL-10途径在肾上皮细胞和巨噬细胞之间 防止肥胖症中的慢性和急性肾脏损伤。此外，AT2R改变了巨噬细胞的平衡 M1和M2类型限制肾脏损伤并促进修复，特别是在肥胖症的AKI中。测试这个 假设，AIM 1指示确定通过IL-10途径肾脏AT2R减少局部炎症和 保护肾脏免受肥胖症的慢性损伤。 AIM 2将研究AT2R激活减弱AKI和 通过巨噬细胞极性向M2型促进肾脏修复。 Unphrctomized肥胖Zucker大鼠 将用于慢性肾脏损伤并置于正常盐水上，并受到缺血/再灌注（I/R） 对于Aki。通过使用shRNA质粒DNA，将实现AT2R和IL-10的肾脏特异性敲低 封装在微泡技术中，以研究肾脏ATNEY ATNNEY AT2R和IL-10在Reno保护，抗 - 炎症和肾脏修复。为了定义AT2R性别偏差，研究了雌激素在 包括AT2R介导的雌性培养培训。最先进的技术将被采用 确定肾损伤和功能的生化，组织学和分子结果。提议 研究将阐明肾脏AT2R在肾脏保护中的新作用，并将其识别为一种新型治疗 防止和修复肾脏损伤的目标。