New Insights in Mechanisms of Renal Injury

肥胖的影响已经在慢性肾脏疾病(CKD)合并糖尿病的进展中得到了很好的描述， 高血压，甚至是IgA肾病，然而肥胖是如何导致进行性肾脏的基础 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是可以接受的。胰岛素升高对肾脏的影响就不那么好了 已经成立了。尽管胰岛素抵抗是足细胞损伤的一个关键因素，但胰岛素和胰岛素的作用 近端肾小管上皮细胞的受体尚未得到很好的研究。在我们最近发表的研究中，我们证明了 小鼠肾脏近端肾小管上皮细胞胰岛素受体的缺乏在攻击时具有肾脏保护作用 高脂肪饮食的人。我们进一步证明，胰岛素下调血管内皮细胞中的胱硫酮裂解酶(CSE)。 小鼠肾脏伴有硫化氢生成抑制和AMPK活性降低。这个 减少硫化氢可能是关键的一步，因为添加硫化氢可以恢复AMPK的激活，尽管 在近端肾小管细胞中暴露于胰岛素。在这个新的退伍军人福利提案中，我们将在目标1中检查 AMPK作为胰岛素在肾小管细胞下游的主要途径 在胰岛素受体和AMPK a1或AMPK a2催化亚基的肾小管水平。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受到调节 特异性近端小管胰岛素受体基因敲除(KPTIRKO)小鼠。肾脏代谢物的鉴定， 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的结合，并指示 肾小管AMPK活性状态。在目标2中，我们将检验胰岛素快速刺激的假设 蛋白酶体通过调节NOX4活性降解CSE。

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.