Vascular ANGII/Jak2 in progression of renal disease

血管 ANGII/Jak2 在肾脏疾病进展中的作用

• 批准号: 8386039
• 负责人: CHRISTINE BAYLIS
• 金额: $ 20.21万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386039
• 关键词: Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Area; Blood; Blood Pressure; Blood Vessels; Chronic; Chronic Kidney Failure; Clinical Research; Coupling; Creatinine clearance measurement; Data; Development; Disease Progression; Dose; Drug Combinations; Epithelial; Functional disorder; Future; Genotype; Goals; Gold; Harvest; Hour; Hydralazine; Hypertension; Immunohistochemistry; Infusion procedures; Injury; Investigation; Janus kinase 2; Kidney; Kidney Diseases; Kidney Transplantation; Knock-out; Knockout Mice; Location; Measurement; Mediating; Messenger RNA; Metabolic; Modeling; Mus; Nitric Oxide; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Pilot Projects; Plasma; Play; Positioning Attribute; Process; Production; Proteins; Proteinuria; Reactive Oxygen Species; Renal Tissue; Renal function; Renin; Renin-Angiotensin System; Renin-Angiotensin-Aldosterone System; Reserpine; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Source; System; Telemetry; Testing; Therapeutic Agents; Tissues; Transcript; Transgenic Mice; Translating; Transplantation; Vascular Smooth Muscle; drinking water; hypertension treatment; inhibitor/antagonist; innovation; instrument; kidney vascular structure; novel; novel therapeutics; pressure; research study; response; small molecule; standard care; thiazide

DESCRIPTION (provided by applicant): It is well known that inappropriate angiotensin II (ANGII) activation plays a primary pathogenic role in the progression of chronic kidney disease (CKD), irrespective of the initiating cause. The source of the ANGII (vascular, renal epithelial, etc) and the signaling pathways that are involved in this process are poorly understood. The goal of this application is to establish the importance of the coupling between angiotensin II (ANGII) signaling and Janus kinase 2 (Jak2) in vascular smooth muscle cells (VSMC) in the progression of CKD. This pilot project involves the phenotyping of a novel conditional knockout mouse that lacks Jak2 expression within VSMC and is resistant to the development of chronic ANGII-induced hypertension, implicating a primary role of the vascular smooth muscle Jak2 signaling pathway. Our preliminary studies have demonstrated that the VSMC Jak2 null mouse is also highly resistant to chronic ANGII-induced CKD and this beneficial effect is pressure independent. Thus, we hypothesize that it is the renal actions of ANGII, mediated by Jak2, that are largely responsible for the hypertension and CKD associated with high dose chronic ANGII infusion. The first specific aim extends our observations on the chronic ANGII-infusion model of CKD and specifically investigates the role of VSMC-derived Jak2 on renal function and dysfunction during ANGII- induced CKD. The second specific aim uses a kidney cross transplant model and an intrarenal infusion of a selective Jak2 inhibitor to determine whether VSMC-derived Jak2 in the kidney is responsible for ANGII- mediated hypertension and CKD. In the third specific aim, we will determine if the deleterious actions of VSMC-derived Jak2, in response to chronic ANGII infusion, involve inhibition of nitric oxide (NO) and increases in reactive oxygen species (ROS). All experiments will be done on an FVB background. These mice are susceptible to ANGII-induced hypertension and CKD. The VSMC Jak2 null genotype is SM22¿Cre(+);Jak2fl/fl while the control genotype is SM22¿Cre(-);Jak2fl/fl. All animals studied will be chronically instrumented for blood pressure measurement by telemetry, will have metabolic cage studies to follow the development of proteinuria and total NO production and tissues/blood will be harvested for assessment of renal pathology, 24 hour creatinine clearance (Ccr), determinants of NO and ROS production, plasma and renal tissue ANGII and levels of components of the intrarenal renin angiotensin system at the transcript, protein and activity level. Collectively, our proposed studies will (i) provide evidence for our hypothesis (ii) provid a better mechanistic understanding for how VSMC-derived Jak2 mediates CKD in response to chronic ANGII and (iii) position us to translate our investigation into a clinical study for the us of Jak2 inhibitors for the treatment of hypertension and CKD. PUBLIC HEALTH RELEVANCE: Angiotensin II plays a key role in the progression of many forms of kidney disease and this application uses a unique transgenic mouse and novel drug to investigate how angiotensin II signaling in the blood vessel (vascular smooth muscle) contributes to this injury process.

描述（由应用提供）：众所周知，不适当的血管紧张素II（ANGII）激活在慢性肾脏疾病（CKD）的进展中起主要的致病作用，而与起始原因无关。该过程中所涉及的Angii（血管，肾上皮等）和信号通路的来源很少。该应用的目的是确定血管紧张素II（ANGII）信号传导与Janus激酶2（JAK2）在CKD进展中耦合的重要性。该试点项目涉及一种新型有条件敲除小鼠的表型，该小鼠在VSMC中缺乏JAK2表达，并且对慢性血管诱导的高血压的发展具有抵抗力，这隐含了血管平滑肌JAK2信号通路的主要作用。我们的初步研究表明，VSMC JAK2 NULL小鼠对慢性Angii诱导的CKD具有高度耐药性，并且这种有益效应与压力无关。这就是我们假设是由JAK2介导的Angii的肾作用，主要负责与高剂量的慢性Angii输注相关的高血压和CKD。第一个特定目的扩展了我们对CKD慢性血管融合模型的观察结果，并专门研究了VSMC衍生的JAK2在ANGII诱导的CKD期间对肾功能和功能障碍的作用。第二个特定目的使用肾脏跨移植模型和选择性JAK2抑制剂的肾内输注来确定肾脏中VSMC衍生的JAK2是否负责血管介导的高血压和CKD。在第三个特定目的中，我们将确定响应慢性血管静脉输注的VSMC衍生JAK2的有害作用是否涉及抑制一氧化氮（NO）和活性氧（ROS）的增加。所有实验将在FVB背景下完成。这些小鼠容易受到血管诱导的高血压和CKD的影响。 VSMC JAK2 NULL基因型为SM22 cre（+）； JAK2FL/FL，而对照基因型为SM22？CRE（ - ）; JAK2FL/FL。 All animals studiod will be chronically instrumented for blood pressure measurement by telemetry, will have metabolic cage studies to follow the development of proteinuria and total NO production and tissues/blood will be harvested for assessment of renal pathology, 24 hours creationin clearance (Ccr), determines of NO and ROS production, plasma and renal tissue ANGII and levels of components of the intrarenal renin angiotensin system at the转录本，蛋白质和活性水平。总的来说，我们提出的研究将（i）为我们的假设提供证据（ii）为VSMC衍生的JAK2如何介导CKD的响应慢性Angii和（iii）如何将我们的研究转化为JAK2抑制剂的临床研究，以对JAK2抑制剂的治疗来治疗高血压和CKD的临床研究。 公共卫生相关性：血管紧张素II在多种形式的肾脏疾病的进展中起关键作用，该应用使用独特的转基因小鼠和新型药物来研究血管中血管紧张素II信号（血管平滑肌）如何有助于这种损伤过程。