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)是由于各种原因导致的肾功能的突然丧失，这可能会导致 到几个并发症，包括代谢性酸中毒，高钾血症，尿毒症，增加 细胞外液体量，和死亡。外源性给予表皮生长因子(EGF) 已被发现可以促进再生和修复肾小管细胞，并加速恢复 肾毒素诱导的急性肾损伤后肾功能的变化。另一方面，激活 表皮生长因子受体(EGFR)也参与慢性肾脏的发生发展 疾病(CKD)。显然，EGF/EGFR的激活扮演着一个不确定的角色，因为它可以是 AKI后对肾功能有利或有害。更好地理解其在 因此，肾脏非常重要。在本研究中，我们假设核糖核酸酶L是一个非常 肾功能的重要调节因子，在基本情况下，允许ADAM10- 依赖肾小管上皮细胞生长因子分泌，调节正常肾脏发育和生长。 在AKI和肾小管损伤的情况下，这些相同的通路对于修复是必不可少的，但 需要适当下调，以防止AKI向CKD过渡。这个 假设是基于我们最近获得的结果：1)肾脏大小显著 与野生型小鼠相比，核糖核酸酶L基因敲除小鼠的表达减少，这一点更加明显 衰老后；2)核糖核酸酶L基因敲除小鼠尿表皮生长因子完全消失；3)核糖核酸酶L介导 去整合素和金属蛋白酶结构域10(ADAM10)的表达和成熟 跨膜金属蛋白水解酶对EGF前体的脱落和释放 4)核糖核酸酶L基因敲除小鼠比野生型L基因敲除小鼠恢复得更快 小鼠从叶酸(FA)诱导的AKI通过激活PI3K/AKT通路。具体的 目的是研究核糖核酸酶L调节表皮生长因子分泌的分子机制 尿液中核糖核酸酶L在正常和病理条件下对肾功能的影响 探讨核糖核酸酶L是否参与急性心肌梗死向慢性肾脏病的转变。我们的研究将提供新的见解 核糖核酸酶L如何调节表皮生长因子配体家族的动态平衡和活化 受体在肾脏发育、衰老、生理学和病理生理学中起着至关重要的作用。多数 重要的是，该项目将为更多的本科生提供一个独特的机会 接受与疾病相关的基础科学方面的培训。