New Insights in Mechanisms of Renal Injury

肾损伤机制的新​​见解

• 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
• 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

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.

肥胖的影响已经在慢性肾病（CKD）伴糖尿病的进展中得到了很好的描述， 高血压，甚至伊加肾病，然而，肥胖如何有助于进行性肾脏疾病的基础， 疾病不清楚。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是可接受的。胰岛素升高对肾脏的影响不太好 确立了习虽然胰岛素抵抗是足细胞损伤的关键因素，但胰岛素和胰岛素受体的作用可能与足细胞损伤有关。 近端肾小管细胞中的受体尚未得到很好的研究。在我们最近发表的研究中， 小鼠肾脏近端小管细胞中胰岛素受体的缺乏在激发时具有肾脏保护作用 吃高脂肪食物我们进一步证明了胰岛素下调了胰岛素依赖性前列腺增生中的胱抑素裂解酶（CSE）。 小鼠肾脏，同时抑制硫化氢生成和降低AMPK活性。的 减少硫化氢可能是关键步骤，因为添加硫化氢恢复AMPK活化， 暴露于近端肾小管细胞中的胰岛素。在这个新的VA Merit提案中，在目标1中，我们将研究以下方面的作用： AMPK作为肾小管细胞中胰岛素下游的主要途径，通过检查缺乏AMPK的小鼠， 在胰岛素受体和AMPK α 1或AMPK α 2催化亚基中的小管水平。用我们的新方法 空间代谢组学，我们将确定关键代谢物是否在肾小管水平上受到调节 特异性近端肾小管胰岛素受体敲除（KPTIRKO）小鼠。鉴别肾脏中的代谢物， 血液和尿液将指示循环生物标志物是否可以指示肾小管IR的接合， 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 蛋白酶体通过调节Nox4活性降解CSE。