The role of RNase L in kidney function

急性肾损伤（阿基）是由各种原因引起的肾功能突然丧失，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 细胞外液量和死亡表皮生长因子（EGF）的作用 已发现可增强肾小管细胞的再生和修复，并加速恢复 缺血后和肾毒素诱导的阿基中的肾功能。另一方面，激活 表皮生长因子受体（EGFR）也有助于慢性肾脏疾病的发展和进展 慢性肾病（CKD）。显然，EGF/EGFR的激活起着不确定的作用，因为它可以是 对阿基后的肾功能有益或有害。更好地了解其在 因此，肾是重要的。在这项研究中，我们假设RNase L是一种非常重要的 重要的调节肾功能，在基础情况下，通过允许ADAM 10- 依赖肾小管分泌EGF，调节正常肾脏发育和生长。 在阿基和肾小管损伤的背景下，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阿基向CKD的转变。的 这一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，RNase L敲除小鼠中降低，这更明显 衰老后; 2）尿EGF在RNase L敲除小鼠中完全消除; 3）RNase L介导的 解整合素和金属蛋白酶结构域10（ADAM 10）， 负责脱落和释放EGF前体的跨膜金属蛋白酶 RNase L敲除小鼠的恢复速度比RNase L野生型快得多 小鼠通过激活PI 3 K/AKT通路而免受叶酸（FA）诱导的阿基。具体 目的是研究RNase L调节EGF分泌的分子机制 以及RNase L在正常和病理条件下肾功能中的作用， 探索RNase L是否参与阿基向CKD的转变。我们的研究将提供新的见解 RNA酶L如何调节EGF家族配体的稳态和EGF受体的激活。 受体，其在肾脏发育、衰老、生理学和病理生理学中至关重要。最 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培训。

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.