#4966 CELLULAR PRION PROTEIN ACTIVATES THE TBK1-IRF3 SIGNALING PATHWAY TO AGGRAVATE RENAL FIBROSIS

Abstract Background and Aims Chronic kidney disease (CKD) is an irreversible degenerative characterized by gradual loss of renal function, contributing to high morbidity mortality as well heavy economic cost society. Clinically, there are few available strategies slow CKD progression. Because the uremic phenotypes include many features aging, considered a premature aging syndrome. Neurodegenerative diseases, such Alzheimer's disease, Parkinson's extensively studied aging-related in which cytotoxic proteins misfolding aggregation neural cells main characteristic. The prion protein tightly linked development diseases. Interestingly, remarkable elevation cellular (PrPC) urine plasma patients was reported. However, role PrPC pathogenesis diseases remains largely unknown. aim current study investigate fibrosis. Methods Immunohistochemistry staining conducted evaluate expression biopsies from patients. Enzyme immunosorbent assay (ELISA) performed detect urinary Animal model fibrosis induced unilateral ureteral occlusion (UUO). Western blot, real time PCR immunofluorescence were distribution PrPC. Proximal tubule specific Prnp knockout mice (PEPCK-Prnp-KO) constructed explore pathogenic Primary proximal tubular epithelial (PTCs) overexpressed collected for RNA-seq analysis. TBK1 inhibitor amlexanox, IRF3 siRNA used block TBK1-IRF3 pathway rat (NRK-52E), respectively. Amlexanox administered orally UUO mice. H&E, Masson Sirius red estimate pathology. Results levels both elevated significantly correlated with severity interstitial decline eGFR. increased, aggregated tubules fibrotic tissues UUO. Compared wild-type littermates, PEPCK-Prnp-KO showed reduced extracellular matrix accumulation inflammation at day 7 after provokes profibrotic response via pathway. amlexanox or silencing endogenous inhibited PrPC-induced profibrogenic phenotypic transformation NRK-52 cells. attenuated Conclusion Our experimental results indicate that PrPC-TBK1-IRF3 plays detrimental thus contributes Blocking activation plausible strategy therapeutic intervention chronic disorders.