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: 10543829
• 负责人: BABU Joseph PADANILAM
• 金额: $ 45.43万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543829
• 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; Ischemia; Kidney; Knockout Mice; Knowledge; Liver; Lung; Macrophage; Mediating; Medical; Modeling; Nephrectomy; Nerve; Norepinephrine; Organ; Pathogenicity; Pathway interactions; Phenotype; Play; Population; Process; Publishing; RENBP gene; Receptor Activation; Receptor Inhibition; Receptor Signaling; 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; clinical translation; combinatorial; cytokine; effective therapy; efficacious treatment; fibrogenesis; genetic approach; in vitro Model; in vivo; inhibitor; innovation; interstitial; kidney cell; kidney fibrosis; long-term sequelae; mouse model; neuroregulation; novel; pharmacologic; prevent; protein activation; recruit; renal ischemia; single molecule; standard of care; transcriptomics; translational potential

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 急性肾脏损伤（AKI）被认为是进行性慢性肾脏疾病（CKD）的主要风险。但是， AKI导致纤维发生并最终导致终末期肾脏疾病（ESRD）2的机制尚未定义，应得 对于驱动纤维化的主要信号的有限了解，CKD的有效治疗是一种主要的未经医疗 需要。我们的数据表明，肾脏去神经可以预防肾纤维化和炎症的新范式 肾纤维化模型：5/6肾切除术（5/6NX），单侧输尿管异常（UUO）和缺血性肾损伤（IRI）。 我们的数据表明，肾神经衍生的因子去甲肾上腺素（NE），通过α2-肾上腺素受体（α2-ar）信号传导 在启动纤维化和注射及其抑制前或伤害后可以降低纤维化 这些CKD模型中有70％。这一发现令人惊讶，因为大多数针对单个分子或途径的实验策略 很少将纤维化降低超过50％。这项研究的总体目标是通过 通过α2-AR的NE信号传导诱导纤维化并确定抑制α2-AR亚型的治疗潜力 或其在IRI模型中预防肾纤维发生和炎症的下游信号通路。我们的初步 研究表明，通过α2-AR的NE信号传导影响肾近端块茎细胞中血管紧张素原（AGT）的表达 （RPTC）通过激活CAMP响应元件结合蛋白（CREB）。此外，简单抑制α2AR 亚型A和C添加到受保护免受注射和纤维化的保护中，表明亚型特异性信号传导激活 与Creb-agt轴平行的途径可能促进间质纤维化和CKD。基于这些数据，我们的中央 假设是NE激活α2AR-SUBTTIPES特异性信号途径以诱导间质纤维化及其抑制作用 可以预防IRI的长期后遗症。此外，α2AR激活调节平行途径，包括成纤维细胞激活 和Mφ浸润，激活和Mφ表型转换，并激活肾素 - 血管紧张素II信号传导（RAS）信号传导 促进纤维化的途径。在特定目标1中，使用遗传和药物方法，我们将描述 三种α2-ar亚型（a，b和c）的功能和机械作用，以及它们抑制对肾脏的影响 IRI模型中的纤维发生。使用转录组轮廓，我们将确定重叠与特定途径 α2AR亚型并识别组合抑制后提供额外保护的信号传导分子。在 具体目标2，我们将剖析α2-AR亚型（S）细胞特异性作用（PTC与Mφ与成纤维细胞）在 成纤维细胞分化，Mφ行为或Mφ开关和管状损伤中的细胞因子分泌。在特定的目标3中，我们将 识别激活Creb和Agt信号传导的α2-ar亚型/s，并确定AGT的抑制是否阻止 IRI模型中的炎症和纤维化。这些研究具有很高的意义，因为它们将将α2-ar定义为主要 信号分子调节肾脏间隙中实施的几个关键致病分子和过程 纤维发生，包括巨噬细胞和成纤维细胞激活和RAS信号传导。在这方面，我们的研究立即 临床翻译潜力，因为α2AR抑制剂已经在其他条件下临床使用，并且可以适应 迅速以防止CKD中的纤维化进展，并在包括肝脏，肺和心脏在内的其他器官中可能出现。