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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要急性肾损伤（AKI）被认为是进行性慢性肾病（CKD）的主要风险。 AKI 导致纤维形成并最终导致终末期肾病 (ESRD)2 的机制尚不明确，因为由于对驱动纤维形成的主要信号的了解有限，有效治疗 CKD 是一个主要的未满足的医学领域我们的数据表明了肾去神经支配可以预防肾纤维化和炎症的新范例。肾纤维化模型：5/6肾切除术（5/6Nx）、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) 通过 α2 肾上腺素受体 (α2-AR) 发出信号在启动纤维发生和炎症中起关键作用，损伤前或损伤后抑制它可以减少纤维化约 70% 在这些 CKD 模型中这一发现是惊人的，因为大多数实验策略都针对单个分子或通路。很少能实现纤维化减少超过 50%，我们这项研究的总体目标是通过以下方式描述其机制。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下游信号通路在 IRI 模型中预防肾纤维化和炎症的作用。研究表明，NE 信号通过 α2-AR 诱导肾近端肾小管细胞中血管紧张素原 (AGT) 的表达 (RPTC) 通过激活 cAMP 反应元件结合蛋白 (CREB) 进一步同时抑制 α2AR。 A 和 C 亚型额外保护免受炎症和纤维化，表明亚型特异性信号传导的激活与 CREB-AGT 轴平行的途径，可能促进间质纤维化和 CKD。根据这些数据，我们的中心。假设是 NE 激活 α2AR 亚型特异性信号通路以诱导间质纤维化及其抑制可以预防 IRI 的长期后遗症此外，α2AR 激活可调节平行途径，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) 信号传导在具体目标 1 中，我们将利用遗传和药理学方法来描述促进纤维形成的途径。三种 α2-AR 亚型（A、B 和 C）的功能和机制作用，以及它们对肾脏的抑制作用使用 IRI 模型中的纤维发生，我们将识别之间的重叠途径和特定途径。 α2AR 亚型并鉴定在组合抑制后提供额外保护的信号分子。具体目标 2，我们将剖析 α2-AR 亚型细胞特异性作用（PTC 与 Mφ 与成纤维细胞）在在具体目标 3 中，我们将研究成纤维细胞分化中的细胞因子分泌、Mφ 行为或 Mφ 转换和肾小管损伤。识别激活 CREB 和 AGT 信号传导的 α2-AR 亚型，并确定抑制 AGT 是否可以预防 IRI 模型中的炎症和纤维化具有重要意义，因为它们将 α2-AR 定义为主要的。调节与肾间质有关的几种关键致病分子和过程的信号分子纤维发生包括巨噬细胞和成纤维细胞激活以及RAS信号传导，在这方面我们的研究具有直接意义。临床转化潜力，因为 α2AR 抑制剂已在其他病症的临床使用中并且可以进行调整快速预防 CKD 以及其他器官（包括肝、肺和心脏）纤维化的进展。