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Role of DPP4 in Kidney Inflammation and Injury

DPP4 在肾脏炎症和损伤中的作用

基本信息

批准号：
10552562
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552562
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 Experimental Designs 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 Macrophage Measurement Mediating Medicare Memory Modeling Mononuclear Morbidity - disease rate Mus Nephrectomy Nephrons Non obese Obesity Obesity Epidemic Oligopeptides Overweight Patients Peptides Persons Pharmaceutical Preparations Plasma Play Population Prevention Production Proteins Proteinuria Proximal Kidney Tubules Renal dialysis Renin-Angiotensin System Reporting Rodent Model Role Signal Transduction Sodium Sorting Sucrose Surface T-Lymphocyte Therapeutic Agents Translating Tubular formation absorption cytokine diabetic diabetic patient fatty acid metabolism feeding hypertensives immune activation improved inhibitor insight mortality novel novel therapeutics pharmacologic prevent repaired standard of care western diet

项目摘要

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.

项目概要/摘要由于患有慢性肾脏病（CKD）的人数不断增加，慢性肾脏病（CKD）的发病率正在增加。肥胖 (33%) 或糖尿病 (9%) 或两者兼而有之。在相当大比例的肥胖糖尿病受试者中，慢性肾病可能与非肥胖糖尿病受试者相比，进展为终末期肾病 (ESRD) 和透析的速度更快。终末期肾病的护理患者（占医疗保险人口的 1%）以不成比例的方式消耗医疗保险资金（7%）。因此，预防 CKD 进展为 ESRD 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。然而，这些药物并不足以阻止许多受试者进展为 ESRD，并且需要新的治疗药物。 DPP4抑制剂由于最近的数据显示糖尿病和慢性肾病（CKD）有所改善，因此很容易被置于糖尿病和慢性肾病的交叉点糖尿病合并 CKD 患者的蛋白尿（SAVOR-TIMI 试验和动物模型）。尼斯塔拉博士和其他人显示 DPP4 抑制剂可能具有独立于血压或血糖的肾脏特异性作用改进。然而，DPP4 抑制剂介导的肾脏益处的机制相对较少。未知。如果 DPP4 抑制剂用于预防肾脏疾病的进展，其生物学功能需要更好地了解 DPP4 在肾脏中的作用。数据支持 DPP4 可能调节钠的观点肾近端小管的吸收和白蛋白/寡聚肽的内吞作用。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）呈递细胞 [APC]），根据肥胖者和血浆中脂肪库的发现，可能介导炎症来自糖尿病患者。肾小管间质炎症和纤维化在肾病的进展中起着重要作用肥胖和糖尿病背景下的 CKD，重要的是，Nistala 博士发现 DPP4 活性在肥胖/糖尿病小鼠的肾脏和近端肾小管中的表达水平较高。因此，本项目重点研究 DPP4 在近曲小管和肾脏免疫系统中的作用肥胖/糖尿病。这些实验旨在解决肥胖的中心假设诱导的近端小管 DPP4 激活会激发促炎性免疫反应，从而导致肾小管间质纤维化和肾脏疾病的进展。为了解决这个假设，DPP4 将通过高蔗糖/高脂肪（西方饮食）喂养有或没有 DPP4 缺乏的小鼠来激活。在目标 1 中，西方饮食在近曲小管 DPP4 激活和肾小管功能障碍中的作用将通过使用近曲小管特异性 DPP4 缺失。目标2，近曲小管DPP4在肾脏免疫系统中的作用将检查激活情况。在目标 3 中，近曲小管 DPP4 诱导的免疫系统激活在将研究肾小管间质纤维化和肾脏疾病进展。预计由此产生的结果该项目将对肥胖/糖尿病的肾损伤和炎症机制产生独特的见解最终目标是将这些发现转化为有意义的治疗方法。