New Insights in Mechanisms of Renal Injury

肾损伤机制的新见解

基本信息

批准号：
10487741
负责人：
Kumar Sharma
金额：
--
依托单位：
SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2026-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10487741
关键词：
6-phosphogluconate Adipose tissue Affect Age Biological Markers Blood Blood Glucose Catalytic Domain Cells Chronic Kidney Failure Complication Complications of Diabetes Mellitus Cystathionine Data Diabetes Mellitus Diabetic Nephropathy Disease Progression Enzymes Exposure to Fatty acid glycerol esters General Population Generations HDAC6 gene Heart High Fat Diet High Prevalence Histology Hydrogen Sulfide Hypertension IGA Glomerulonephritis Incidence Inflammatory Injury Injury to Kidney Insulin Insulin Receptor Insulin Resistance Kidney Kidney Diseases Knock-out Knockout Mice Lipids Liver Lyase Mediating Mediator Methods Modeling Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated kidney disease Organ Outcome Pathway interactions Patients Play Population Production Proteins Publishing Receptor Inhibition Regulation Renal Hypertension Role Signal Transduction Techniques Testing Therapeutic Tissues Toxic effect Tubular formation Urine cell injury circulating biomarkers diabetic in vivo inhibitor insight insulin sensitivity insulin signaling knock-down metabolomics non-diabetic novel podocyte protective effect restoration sensor theories

项目摘要

The impact of obesity has been well described in the progression of chronic kidney disease (CKD) with diabetes, hypertension and even IgA nephropathy, however the basis for how obesity contributes to progressive kidney disease is unclear. Obesity is often associated with elevated insulin levels and the state of insulin resistance at the level of muscle and adipose tissue is accepted. The impact of elevated insulin on the kidney is less well established. Although insulin resistance is a key contributor to podocyte injury, the role of insulin and the insulin receptor in the proximal tubular cell has not been well studied. In our recent published study we demonstrate that lack of the insulin receptor in proximal tubular cells of the mouse kidney was renoprotective upon challenge with a high fat diet. We further demonstrated that insulin down-regulates the cystathione y lyase (CSE) in the mouse kidney with concomitant inhibition of hydrogen sulfide generation and reduction of AMPK activity. The reduced hydrogen sulfide may be a key step as addition of hydrogen sulfide restores AMPK activation despite exposure to insulin in proximal tubular cells. In this new VA Merit proposal, in aim 1 we will examine the role of AMPK as the major pathway that is downstream of insulin in tubular cells by examining mice that are deficient in the insulin receptor and AMPK a1 or AMPK a2 catalytic subunits at the tubular level. With our new method of spatial metabolomics we will determine whether key metabolites are regulated at the tubular level in the kidney specific proximal tubular insulin receptor knockout (KPTIRKO) mouse. Identification of metabolites in the kidney, blood and urine will indicate if a circulating biomarker could indicate engagement of the tubular IR and indicate the status of tubular AMPK activity. In aim 2, we will test the hypothesis that insulin rapidly stimulates proteasomal degradation of CSE via regulation of Nox4 activity.

肥胖对慢性肾病 (CKD) 合并糖尿病的进展已得到充分描述，高血压甚至 IgA 肾病，然而肥胖如何导致肾病进展的基础疾病尚不清楚。肥胖通常与胰岛素水平升高和胰岛素抵抗状态有关肌肉和脂肪组织的水平被接受。胰岛素升高对肾脏的影响不太好已确立的。尽管胰岛素抵抗是足细胞损伤的关键因素，但胰岛素和胰岛素的作用近端肾小管细胞中的受体尚未得到充分研究。在我们最近发表的研究中，我们证明小鼠肾脏近端肾小管细胞中缺乏胰岛素受体在受到攻击时具有肾脏保护作用高脂肪饮食。我们进一步证明胰岛素下调胱硫醚 y 裂解酶 (CSE) 小鼠肾脏，同时抑制硫化氢产生并降低 AMPK 活性。这减少硫化氢可能是一个关键步骤，因为添加硫化氢可以恢复 AMPK 活化，尽管近端肾小管细胞暴露于胰岛素。在这个新的 VA Merit 提案中，在目标 1 中，我们将研究通过检查缺陷小鼠，发现 AMPK 是肾小管细胞中胰岛素下游的主要途径存在于肾小管水平的胰岛素受体和 AMPK a1 或 AMPK a2 催化亚基中。通过我们的新方法空间代谢组学我们将确定关键代谢物是否在肾小管水平受到调节特异性近端肾小管胰岛素受体敲除（KPTIRKO）小鼠。鉴定肾脏中的代谢物，血液和尿液将表明循环生物标志物是否可以表明肾小管 IR 的参与并表明肾小管 AMPK 活性的状态。在目标 2 中，我们将检验胰岛素快速刺激的假设通过调节 Nox4 活性，蛋白酶体降解 CSE。