The role of RNase L in kidney function

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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.