Neuromodulation of long-term sequelae of ischemic acute kidney injury

缺血性急性肾损伤长期后遗症的神经调节

• 批准号: 10311243
• 负责人: BABU Joseph PADANILAM
• 金额: $ 48.55万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311243
• 关键词: Ablation; Acute Renal Failure with Renal Papillary Necrosis; Adrenergic Receptor; Adult; Affect; Angiotensin II; Angiotensinogen; Apoptotic; Behavior; Blood Pressure; Bone Marrow; Cells; Characteristics; Chronic Kidney Failure; Clinical; Cyclic AMP-Responsive DNA-Binding Protein; Data; Denervation; Development; Disease; Disease Progression; Disease model; End stage renal failure; Event; Experimental Models; Fibroblasts; Fibrosis; Genetic; Goals; Health Care Costs; Heart; Human; Infiltration; Inflammation; Inflammatory; Information Systems; Injury; Injury to Kidney; Kidney; Knockout Mice; Knowledge; Lead; Liver; Lung; Mediating; Medical; Modeling; Nephrectomy; Nerve; Norepinephrine; Organ; Pathogenicity; Pathway interactions; Pharmacology; Phenotype; Play; Population; Process; Publishing; RENBP gene; Receptors, Adrenergic, alpha-2; Renin; Reperfusion Injury; Risk; Role; Scheme; Signal Pathway; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Tubular formation; Ureteral obstruction; Uridine; base; combinatorial; cytokine; effective therapy; efficacious treatment; fibrogenesis; genetic approach; in vitro Model; in vivo; inhibitor/antagonist; innovation; interstitial; kidney cell; kidney fibrosis; macrophage; mouse model; neuroregulation; novel; prevent; protein activation; recruit; single molecule; standard of care; transcriptomics

Project Summary Acute kidney injury (AKI) is recognized as a major risk for progressive chronic kidney disease (CKD). However, the mechanism by which AKI leads to fibrogenesis and ultimately to end-stage renal disease (ESRD)2 is not well defined, Due to limited knowledge of the primary signals that drive fibrogenesis, effective therapy for CKD is a major unmet medical need. Our data indicate the novel paradigm that renal denervation can prevent renal fibrosis and inflammation in three renal fibrogenesis models: 5/6 nephrectomy (5/6Nx), unilateral ureteral obstruction (UUO) and ischemic renal injury (IRI). Our data indicate that the renal nerve-derived factor, norepinephrine (NE), signaling via α2-adrenergic receptor (α2-AR) plays a key role in initiating fibrogenesis and inflammation and its inhibition pre-or post-injury can reduce fibrosis by about 70% in these CKD models. This finding is striking, as most experimental strategies targeting a single molecule or a pathway rarely achieve a reduction of fibrosis of more than 50%. Our overall goal of this study is to delineate the mechanisms by which NE signaling via α2-AR induces fibrosis and determine the therapeutic potential of inhibition of the α2-AR subtype or its downstream signaling pathways in preventing renal fibrogenesis and inflammation in the IRI model. Our preliminary studies indicate that NE signaling via α2-AR induces the expression of angiotensinogen (AGT) in renal proximal tubular cell (RPTC) via activation of cAMP-response element-binding protein (CREB). Further, simultaneous inhibition of α2AR subtypes A and C additively protected from inflammation and fibrosis, suggesting activation of subtype specific signaling pathways, parallel to CREB-AGT axis, that may promote interstitial fibrosis and CKD. Based on these data, our central hypothesis is that NE activates α2AR-subtypes specific-signaling pathways to induce interstitial fibrosis and their inhibition can prevent long term sequelae of IRI. Further, α2AR activation regulates parallel pathways including, fibroblast activation and Mφ infiltration, activation and Mφ phenotypic switching, and activates Renin-Angiotensin II Signaling (RAS) signaling pathways to promote fibrogenesis. In specific aim 1, using genetic and pharmacological approaches, we will delineate the functional and mechanistic role of the three α2-AR subtypes (A, B and C), and the effect of their inhibition on renal fibrogenesis in the IRI-model. Using transcriptomic profile, we will identify overlapping versus specific pathways between the α2AR subtypes and identify the signaling molecules that provides added protection after combinatorial inhibition. In specific aim 2, we will dissect out the distinct role of of α2-AR subtype(s) cell-specific role (PTC vs. Mφ vs fibroblasts) in cytokine secretion in fibroblast differentiation, Mφ behavior or Mφ switching and tubular injury. In specific aim 3, we will identify the α2-AR subtype/s that activates CREB and AGT signaling and determine whether inhibition of AGT prevents inflammation and fibrosis in the IRI model. The studies have high significance as they will define α2-AR as a primary signaling molecule that regulates several of the key pathogenic molecules and processes implicated in the renal interstitial fibrogenesis including macrophage and fibroblast activation and RAS signaling. In this regard, our studies have immediate clinical translational potential, because α2AR inhibitors are already in clinical use in other conditions and could be adapted rapidly to prevent the progression of fibrosis in CKD and plausibly in other organs including the liver, lung and heart.

项目摘要 急性肾损伤（阿基）被认为是进行性慢性肾病（CKD）的主要风险。但 阿基导致纤维化并最终导致终末期肾病（ESRD）2的机制尚未明确，由于 由于对驱动纤维化的主要信号的了解有限，CKD的有效治疗是一个主要的未满足的医疗需求。 需要的我们的数据表明，新的范式，肾去神经支配可以防止肾纤维化和炎症，在三个 肾纤维化模型：5/6肾切除（5/6 Nx）、单侧输尿管梗阻（UUO）和缺血性肾损伤（IRI）。 我们的数据表明，肾神经衍生因子，去甲肾上腺素（NE），信号通过α2-肾上腺素能受体（α2-AR）， 在引发纤维化和炎症中起关键作用，其在损伤前或损伤后的抑制可使纤维化减少约 在这些CKD模型中占70%。这一发现是惊人的，因为大多数针对单个分子或通路的实验策略 很少能达到纤维化减少50%以上。我们这项研究的总体目标是通过以下方式来描述机制： 其中NE信号通过α2-AR诱导纤维化，并决定抑制α2-AR亚型的治疗潜力 或其下游信号通路在预防IRI模型中的肾纤维化和炎症中的作用。我们的初步 研究表明，NE信号通过α2-AR诱导肾近端小管细胞血管紧张素原（AGT）的表达 通过激活cAMP反应元件结合蛋白（CREB），此外，同时抑制α 2 AR 亚型A和C相加保护免于炎症和纤维化，表明亚型特异性信号传导的激活 与CREB-AGT轴平行的信号通路，可能促进间质纤维化和CKD。根据这些数据，我们的中心 假设NE激活α 2 AR亚型特异性信号通路诱导间质纤维化，并抑制其表达 可以预防IRI的长期后遗症。此外，α 2 AR激活调节平行途径，包括成纤维细胞激活 和Mφ浸润，活化和Mφ表型转换，并激活肾素-血管紧张素II信号传导（RAS） 促进纤维化的途径。在具体目标1中，我们将使用遗传学和药理学方法， 三种α2-AR亚型（A、B和C）的功能和机制作用，以及它们的抑制对肾功能的影响。 IRI模型中的纤维化。使用转录组学谱，我们将确定重叠与特定的途径之间的 α2AR亚型，并确定在组合抑制后提供额外保护的信号分子。在 具体目标2，我们将剖析出α2-AR亚型细胞特异性作用（PTC vs. Mφ vs.成纤维细胞）在 成纤维细胞分化、Mφ行为或Mφ转换和肾小管损伤中的细胞因子分泌。具体目标3： 鉴定激活CREB和AGT信号传导的α2-AR亚型，并确定AGT抑制是否阻止 炎症和纤维化。这些研究具有很高的意义，因为它们将α2-AR定义为主要的 调节肾间质中涉及的几种关键致病分子和过程的信号分子 纤维形成包括巨噬细胞和成纤维细胞活化和RAS信号传导。在这方面，我们的研究有直接的意义。 临床转化潜力，因为α2AR抑制剂已经在其他条件下临床使用，可以调整 快速预防CKD中的纤维化进展，并可预防其他器官（包括肝脏、肺和心脏）中的纤维化进展。