Mechanisms of Adaptive and Maladaptive Responses of Renal Epithelium to Injury

肾上皮对损伤的适应性和适应不良反应的机制

• 批准号: 10265419
• 负责人: RAYMOND C. HARRIS
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265419
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Awareness; Cells; Chronic Kidney Failure; Data; Dependence; Development; Diabetes Mellitus; Diabetic Nephropathy; End stage renal failure; Epidermal Growth Factor Receptor; Epithelial; Fibroblasts; Fibrosis; Frequencies; Glycolysis Inhibition; Goals; Grant; Healthcare; Hypertension; In Vitro; Incidence; Injury; Injury to Kidney; Kidney; Kidney Diseases; Lysophosphatidic Acid Receptors; MAPK3 gene; MEKs; Mediating; Mediation; Mediator of activation protein; Mission; Modeling; Mus; Myofibroblast; Natural regeneration; PI3K/AKT; Pathologic; Pathway interactions; Pharmacology; Physiological; Play; Prevalence; Prevention; Production; Receptor Activation; Recovery; Regulation; Research; Role; Severities; Signal Pathway; Signal Transduction; Veterans; aerobic glycolysis; diabetic; epithelial repair; in vivo; inhibitor/antagonist; injured; kidney fibrosis; lysophosphatidic acid; military veteran; novel; paracrine; prevent; receptor-mediated signaling; renal epithelium; response

Abstract There is renewed awareness of the importance of the renal epithelium generally, and the proximal tubule specifically, as both a target and a mediator in chronic kidney diseases (CKD). Numerous studies have highlighted the importance of tubulointerstitial injury as an ultimate driver of progression of kidney disease. There is also increasing evidence that effective recovery of epithelial integrity following acute kidney injury (AKI) is vital to prevent development of CKD (1). Furthermore, recent studies indicate that the proximal tubule is an important target and contributor to development of diabetic nephropathy. Our previous studies have implicated regulated activation of the EGF receptor (EGFR) in the proximal tubule as an important mediator of recovery from AKI (3) (4) and persistent aberrant EGFR activation as a significant contributor to pathologic development of tubulointerstitial fibrosis in response to hypertension and diabetes (4, 5). Although our previous studies have identified classic signaling pathways, such as the MEK/ERK1/2 and PI-3K/AKT pathways, immediately downstream of EGFR activation in mediation of these responses, the ultimate effectors of EGFR signaling that mediate the regeneration following acute injury and the aberrant responses leading to tubulointerstitial fibrosis have not been adequately elucidated. In this regard, we have recently found evidence for an important role for the HIPPO/YAP pathway in the mediation of EGFR's effects in both proximal tubule diabetic injury and in recovery from AKI (2) and preliminary data). Aims 1 and 2 will utilize in vivo studies with both genetically modified mice and specific pharmacologic inhibitors and targeted in vitro studies to elucidate roles and mechanisms of EGFR-dependent proximal tubule YAP activation and function in both AKI (Aim 1) and CKD (Aim 2). In Aim 3, we will employ novel models of proximal tubule- directed tubulointerstitial fibrosis to investigate the crosstalk between the tubule epithelium and renal fibroblasts. We hypothesize that aberrant proximal tubule production of lysophosphatidic acid (LPA) plays an important paracrine role to transform quiescent renal fibroblasts into active myofibroblasts. We also hypothesize that renal fibroblasts develop a dependence upon aerobic glycolysis (“Warburg phenomenon”) and that inhibition of glycolysis in these cells will prevent myofibroblast transformation and decrease development of tubulointerstitial fibrosis. There are three specific aims: Aim I Determine the Role of EGFR Activation of the Hippo/YAP Pathway in Recovery From Acute Kidney Injury Aim 2 Determine the Role of Hippo/YAP Signaling in EGFR-Mediated Tubulointerstitial Fibrosis Aim 3 Determine the Role of EGFR in Mediating Myofibroblast Transformation and Proliferation The ultimate goal of these studies is to understand physiologic regulation of proximal tubule regeneration and the pathophysiologic mechanisms mediating the development of progressive tubulointerstitial fibrosis and to identify new targets for prevention and treatment of renal fibrosis.

摘要 人们普遍重新认识到肾上皮的重要性， 在慢性肾脏疾病（CKD）中，近端小管作为靶点和介质。 许多研究强调了肾小管间质损伤作为最终的 肾脏疾病进展的驱动因素。也有越来越多的证据表明， 急性肾损伤（阿基）后上皮完整性的恢复对于预防CKD的发展至关重要 （一）.此外，最近的研究表明，近端小管是一个重要的目标， 糖尿病肾病的治疗方法有哪些 我们以前的研究表明，表皮生长因子受体（EGFR）的调节激活， 近端小管作为阿基恢复的重要介质（3）（4）和持续性异常 EGFR活化是肾小管间质性肾炎病理发展的重要因素 纤维化对高血压和糖尿病的反应（4，5）。尽管我们之前的研究 确定了经典的信号通路，如MEK/ERK 1/2和PI-3 K/AKT通路， 在这些反应的介导中，EGFR激活的下游， EGFR信号传导的效应物，其介导急性损伤后的再生， 导致肾小管间质纤维化的异常反应尚未充分阐明。在 关于这一点，我们最近发现HIPPO/雅普通路发挥重要作用的证据 在近端小管糖尿病损伤和从糖尿病恢复中， 阿基（2）和初步数据）。目的1和2将利用体内研究， 改良小鼠和特异性药理学抑制剂以及靶向体外研究，以阐明 EGFR依赖的近端小管雅普激活和功能在两种疾病中的作用和机制 阿基（目标1）和CKD（目标2）。在目标3中，我们将采用新的近端小管模型- 定向肾小管间质纤维化，以研究肾小管上皮细胞和 肾成纤维细胞我们假设异常的近曲小管溶血磷脂的产生 酸性磷酸酶（LPA）在将静止的肾成纤维细胞转化为活跃的肾成纤维细胞中起重要的旁分泌作用。 肌成纤维细胞我们还假设肾成纤维细胞依赖于有氧代谢， 糖酵解（“瓦尔堡现象”），并且抑制这些细胞中的糖酵解将防止 肌成纤维细胞转化和减少肾小管间质纤维化的发展。 有三个具体目标： 目的确定EGFR激活Hippo/雅普通路在急性脑梗死恢复中的作用 肾损伤 目的2确定Hippo/雅普信号通路在EGFR介导的肾小管间质纤维化中的作用 目的3确定EGFR在介导肌成纤维细胞转化和增殖中的作用 这些研究的最终目的是了解近曲小管的生理调节 再生和介导进行性增生发展的病理生理机制 肾小管间质纤维化，并确定预防和治疗肾纤维化的新靶点。