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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：
9885585
负责人：
BABU Joseph PADANILAM
金额：
$ 45.88万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-09 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9885585
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 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

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.

项目总结