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.

急性肾损伤（AKI）是各种原因导致的肾功能突然丧失，这可能导致 多种并发症，包括代谢性酸中毒、高钾血症、尿毒症、增加 细胞外液量和死亡。外源性施用表皮生长因子（EGF） 已发现可增强肾小管细胞的再生和修复并加速康复 缺血后和肾毒素诱导的 AKI 中肾功能的影响。另一方面，激活 EGF 受体 (EGFR) 也有助于慢性肾病的发生和进展 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。更好地了解其监管 因此，肾非常重要。在这项研究中，我们假设 RNase L 是一种非常 在基础情况下，通过允许 ADAM10- 肾功能的重要调节剂 依赖肾小管的 EGF 分泌，调节正常的肾脏发育和生长。 在 AKI 和肾小管损伤的情况下，这些相同的途径对于修复至关重要，但是 需要适当下调以防止 AKI 转变为 CKD。这 假设基于我们最近获得的结果：1) 肾脏大小显着 与野生型小鼠相比，RNase L 敲除小鼠的表达减少，且更为明显 老化后； 2) RNase L敲除小鼠尿液中的EGF完全消失； 3) RNase L 介导 解整合素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 EGF 前体的脱落和释放 在肾脏; 4) RNase L 敲除小鼠的恢复速度比 RNase L 野生型小鼠快得多 叶酸 (FA) 通过激活 PI3K/AKT 通路诱导 AKI 的小鼠。具体的 目的是研究RNase L调节EGF排泄的分子机制 尿液中的 RNase L 以及正常和病理条件下肾功能中的作用以及 探讨 RNase L 是否参与 AKI 向 CKD 的转变。我们的研究将提供新颖的见解 研究 RNase L 如何调节 EGF 配体家族的稳态以及激活 受体，对肾脏发育、衰老、生理学和病理生理学至关重要。最多 重要的是，该项目将为更多本科生提供独特的机会 接受与疾病相关的基础科学培训。