The role of RNase L in kidney function

RNase L 在肾功能中的作用

• 批准号: 10730414
• 负责人: AIMIN ZHOU
• 金额: $ 44.55万
• 依托单位: CLEVELAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730414
• 关键词: Acceleration; Acute Renal Failure with Renal Papillary Necrosis; Age; Aging; Apoptosis; Basic Science; Biochemical; Biological Assay; Blood; Body Fluids; Cell Extracts; Cell Proliferation; Cells; Cessation of life; Chronic Kidney Failure; Cisplatin; Development; Disease; Disintegrins; Electrolytes; Environment; Enzyme-Linked Immunosorbent Assay; Enzymes; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Evaluation; Excretory function; Extracellular Fluid; Family; Fibroblasts; Fluid Balance; Folic Acid; Functional disorder; Genes; Glomerular Filtration Rate; Growth and Development function; Homeostasis; Human; Inflammatory; Injury; Injury to Kidney; Institution; Interferons; Ischemia; Kidney; Knock-out; Knockout Mice; Ligands; Link; Malignant Neoplasms; Mediating; Membrane; Metabolic acidosis; Metalloproteases; Methods; Microscopic; Molecular; Monitor; Mus; Natural Immunity; Natural regeneration; PI3K/AKT; Pathologic; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Play; Potassium; Production; Proteins; Receptor Activation; Recovery; Regulation; Renal function; Renal tubule structure; Research; Ribonucleases; Role; Signal Pathway; Structure; Testing; Therapeutic; Tissues; Training; Tubular formation; Uremia; Urine; Virus; Western Blotting; Wild Type Mouse; cell injury; chemokine; cytokine; epidermal growth factor precursor; hemodynamics; hyperkalemia; injury and repair; insight; interstitial; kidney cell; kidney repair; nephrogenesis; nephrotoxicity; novel; prevent; receptor; release factor; renal damage; repaired; undergraduate student

Acute kidney injury (AKI) is an abrupt loss of kidney function from various causes, which may lead to several complications, including metabolic acidosis, hyperkalemia, uremia, increased extracellular fluid volume, and death. Exogenous administration of epidermal growth factor (EGF) has been found to enhance regeneration and repair renal tubule cells and accelerate the recovery of renal function in post-ischemic and nephrotoxin-induced AKI. On the other hand, activation of the EGF receptor (EGFR) also contributes to development and progression of chronic kidney diseases (CKD). Clearly, the activation of EGF/EGFR plays an uncertain role, as it can be either beneficial or detrimental to renal function after AKI. A better understanding of its regulation in the kidney is, therefore, of importance. In this study, we hypothesize that RNase L is a very important regulator in renal function, under basal circumstances, by permitting ADAM10- dependent tubular EGF secretion, which regulates normal kidney development and growth. In the context of AKI and tubular injury, these same pathways are essential for repair, but need to be appropriately downregulated to prevent the transition of AKI to CKD. The hypothesis is based on the results we recently obtained that 1) kidney size was significantly reduced in RNase L knockout mice compared to wild-type mice, which was more pronounced after aging; 2) urine EGF is completely abolished in RNase L knockout mice; 3) RNase L mediated the expression and maturation of A Disintegrin and Metalloproteinase Domain 10 (ADAM10), a transmembrane metalloprotease responsible for the shedding and releasing of the EGF precursor in the kidney; and 4) RNase L knockout mice were recovered much faster than RNase L wild type mice from folic acid (FA)-induced AKI through activation of the PI3K/AKT pathway. The specific aims are to investigate the molecular mechanisms by which RNase L regulates the EGF excretion in urine and the role of RNase L in kidney function under normal and pathological conditions and explore whether RNase L is involved in AKI to CKD transition. Our study will provide novel insights into how RNase L regulates the homeostasis of the EGF family of ligands and activation of the receptors, which are vital in renal development, aging, physiology and pathophysiology. Most importantly, the project will offer a unique opportunity for more undergraduate students to be trained in the disease-related basic sciences.

急性肾脏损伤（AKI）是由于各种原因突然丧失了肾功能，这可能导致 几种并发症，包括代谢性酸中毒，高钾血症，尿毒症，增加 细胞外流体体积和死亡。表皮生长因子（EGF）的外源给药 已经发现可以增强再生和修复肾小管细胞并加速恢复 缺血后和肾毒素诱导的AKI中的肾功能。另一方面，激活 EGF受体（EGFR）也有助于慢性肾脏的发展和发展 疾病（CKD）。显然，EGF/EGFR的激活起着不确定的作用，因为它可以是 AKI后对肾功能有益或有害。更好地理解其在 因此，肾脏很重要。在这项研究中，我们假设RNase L是一个非常 在基础情况下，肾功能中的重要调节剂通过允许ADAM10- 依赖性管状EGF分泌，调节正常的肾脏发育和生长。 在AKI和管状损伤的背景下，这些相同的途径对于维修至关重要，但是 需要适当地下调以防止AKI向CKD过渡。这 假设基于我们最近获得的结果，即1）肾脏大小显着 与野生型小鼠相比，RNASE L敲除小鼠的减少，这更明显 衰老后； 2）尿液EGF在RNase L敲除小鼠中被完全废除； 3）rNase l介导 崩解蛋白和金属蛋白酶结构域10（ADAM10）的表达和成熟 跨膜金属蛋白酶负责脱落和释放EGF前体 在肾脏； 4）RNase L敲除小鼠的回收速度比RNase L野生型快得多 来自叶酸（FA）的小鼠通过激活PI3K/AKT途径诱导了AKI。具体 目的是研究RNase l调节EGF排泄的分子机制 在尿液和RNase L在正常和病理条件下肾功能中的作用以及 探索RNase L是否参与AKI到CKD转变。我们的研究将提供新颖的见解 rnase如何调节EGF配体家族的稳态和激活 受体，对肾脏发育，衰老，生理和病理生理学至关重要。最多 重要的是，该项目将为更多的本科生提供独特的机会 接受与疾病相关的基本科学的培训。