Role of DPP4 in Kidney Inflammation and Injury

DPP4 在肾脏炎症和损伤中的作用

• 批准号: 10337198
• 负责人: Ravi Nistala
• 金额: $ 16.92万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337198
• 关键词: Acceleration; Address; Albumins; Albuminuria; Angiotensin II; Animal Model; Antigen-Presenting Cells; Atrophic; Biological Process; Blood Glucose; Blood Pressure; Bone Marrow Transplantation; CD44 gene; Carbohydrates; Caring; Cell surface; Cells; Chronic Kidney Failure; Complex; Consumption; Creatinine clearance measurement; Data; Dendritic Cells; Deposition; Diabetes Mellitus; Diabetic mouse; Dialysis patients; Dialysis procedure; Dipeptidyl Peptidases; Dipeptidyl-Peptidase IV; Disease Progression; Disease model; End stage renal failure; Endocytosis; Epidemic; Epithelial Cells; Equilibrium; Event; Expenditure; Extracellular Matrix; Fatty acid glycerol esters; Fibrosis; Functional disorder; Generations; Glomerular Filtration Rate; Goals; Human; Hypertension; ITGAX gene; Immune; Immune response; Immune system; Incidence; Inflammation; Inflammatory; Injury; Injury to Kidney; Kidney; Kidney Diseases; LDL-Receptor Related Protein 2; Lead; Measurement; Mediating; Medicare; Memory; Modeling; Mononuclear; Morbidity - disease rate; Mus; Nephrectomy; Nephrons; Non obese; Obesity; Obesity Epidemic; Oligopeptides; Overweight; Patients; Peptides; Persons; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Population; Prevention; Production; Proteins; Proteinuria; Proximal Kidney Tubules; Renal dialysis; Renin-Angiotensin System; Reporting; Rodent Model; Role; Signal Transduction; Sodium; Sucrose; Surface; T-Lymphocyte; Therapeutic Agents; Translating; Tubular formation; absorption; base; cytokine; design; diabetic; diabetic patient; experimental study; fatty acid metabolism; feeding; hypertensives; immune activation; inhibitor; insight; macrophage; mortality; novel; novel therapeutics; prevent; repaired; standard of care; western diet

Project Summary/Abstract The incidence of chronic kidney disease (CKD) is increasing due to the ever-expanding number of people who are either obese (33%) or diabetic (9%) or both. In a significant proportion of obese-diabetic subjects, CKD may progress to end stage renal disease (ESRD) and dialysis faster than non-obese diabetic subjects. Care of ESRD patients (1% of Medicare population) consumes Medicare dollars in a disproportional manner (7%). Hence, preventing progression of CKD to ESRD is of paramount importance. Currently, the standard of care is to use medications that block/suppress activation of the renin-angiotensin system. However, these medications are not enough to stop progression to ESRD in many subjects and novel therapeutic agents are needed. DPP4 inhibitors are conveniently placed at the intersection of diabetes and CKD due to recent data showing improvement in proteinuria in diabetic patients with CKD (SAVOR-TIMI trial and animal models). Dr. Nistala and others have shown that DPP4 inhibitors may have kidney specific effects independent of blood pressure or blood sugar improvement. However, the mechanisms of DPP4 inhibitor-mediated benefits in the kidney are relatively unknown. If DPP4 inhibitors are to be used for preventing progression of kidney disease, the biological function of DPP4 in the kidney needs better understanding. Data supports the notion that DPP4 may regulate sodium absorption and albumin/oligomeric peptide endocytosis in proximal tubules of the kidney. In addition, DPP4 is a co-stimulatory molecule for T-lymphocytes, activates mononuclear cells (including macrophages and antigen presenting cells [APCs]) and may mediate inflammation based on findings from fat depots in obese and plasma from diabetes patients. Tubulointerstitial inflammation and fibrosis plays an important role in the progression of CKD in the setting of obesity and diabetes and importantly, Dr. Nistala found that DPP4 activity is increased in the kidney and expression levels are higher in the proximal tubules of obese/diabetic mice. Therefore, this project is focused on examining the role of DPP4 in the proximal tubule and kidney immune system in the setting of obesity/diabetes. The experiments are designed to address the central hypothesis that obesity- induced proximal tubule DPP4 activation incites a pro-inflammatory immune response leading to tubulointerstitial fibrosis and progression of kidney disease. To address this hypothesis, DPP4 will be activated via high sucrose/high fat (Western Diet) feeding in mice with or without DPP4 deficiency. In Aim 1, the role of Western diet in activation of DPP4 in the proximal tubule and tubular dysfunction will be studied by using proximal tubule specific deletion of DPP4. In Aim 2, the role of proximal tubule DPP4 in kidney immune system activation will be examined. In Aim 3, the role of proximal tubule DPP4-induced immune system activation in tubulointerstitial fibrosis and kidney disease progression will be studied. It is anticipated that results from this project will yield unique insights into the mechanisms of kidney injury and inflammation in obesity/diabetes with the ultimate goal of translating these findings into meaningful treatments.

项目摘要/摘要 由于不断扩大的人数，慢性肾脏病（CKD）的发生率正在增加 是肥胖（33％）或糖尿病患者（9％）或两者兼而有之。在很大一部分肥胖的糖尿病患者中，CKD可能 比非肥胖的糖尿病患者更快地发展到末期肾脏疾病（ESRD）和透析速度。护理ESRD 患者（占医疗保险人口的1％）以不优体的方式消耗医疗保险（7％）。因此， 防止CKD向ESRD发展至关重要。目前，护理标准是使用 阻断/抑制肾素 - 血管紧张素系统激活的药物。但是，这些药物不是 需要在许多受试者中停止向ESRD进展，并且需要新颖的治疗剂。 DPP4抑制剂 由于最近的数据显示，很方便地将其放置在糖尿病和CKD的交集。 CKD糖尿病患者的蛋白尿（Savor-Timi试验和动物模型）。 Nistala博士等 表明DPP4抑制剂可能具有与血压或血糖无关的肾脏特异性作用 改进。但是，DPP4抑制剂介导的益处的机制相对 未知。如果要使用DPP4抑制剂来预防肾脏疾病的进展 肾脏中的DPP4需要更好的理解。数据支持DPP4可能调节钠的观念 肾脏近端小管中的吸收和白蛋白/寡聚肽内吞作用。此外，DPP4是 T淋巴细胞的共刺激分子激活单核细胞（包括巨噬细胞和抗原 呈现细胞[APC]），并可能基于肥胖和血浆中脂肪库的发现介导炎症 来自糖尿病患者。肾小管间隙炎症和纤维化在进展中起着重要作用 CKD在肥胖和糖尿病的情况下，重要的是，Nistala博士发现DPP4活性在 肥胖/糖尿病小鼠的近端小管中的肾脏和表达水平较高。因此，这个项目 专注于研究DPP4在近端小管和肾脏免疫系统中的作用 肥胖/糖尿病。实验旨在解决肥胖症的中心假设 诱导的近端小管DPP4激活促进了促炎的免疫反应，导致 肾小管纤维化和肾脏疾病的进展。为了解决这一假设，DPP4将是 通过有或没有DPP4缺乏症的小鼠中的高蔗糖/高脂肪（西方饮食）喂养而被激活。在AIM 1中 西方饮食在DPP4激活近端小管和管状功能障碍中的作用将通过使用 DPP4的近端小管特异性缺失。在AIM 2中，近端小管DPP4在肾脏免疫系统中的作用 将检查激活。在AIM 3中，近端小管DPP4诱导的免疫系统激活的作用 将研究肾小管间质纤维化和肾脏疾病进展。预计从中结果 项目将对肥胖/糖尿病的肾脏损伤机制和炎症机制产生独特的见解。 将这些发现转化为有意义的治疗方法的最终目标。