Condensation of cellular prion protein promotes renal fibrosis through the TBK1-IRF3 signaling axis.

Abstract

Cellular prion protein (PrP^C), known for its pathological isoform in prion diseases such as Creutzfeldt-Jakob disease, is primarily expressed in the nervous system but has also been detected in the blood and urine of individuals with renal dysfunction. However, the role of PrP^C in the development of renal disease is unexplored. Here, we showed that PrP^C was up-regulated in fibrotic renal lesions in biopsies from patients with chronic kidney disease (CKD), predominantly in proximal tubular epithelial cells (PTECs). Furthermore, renal expression of PrP^C was positively correlated with the severity of renal failure and the decline in estimated glomerular filtration rate in patients with CKD. In mice, tubular-specific deletion of PrP^C mitigated renal fibrosis induced by unilateral ureteral obstruction (UUO) or unilateral ischemia-reperfusion injury (UIRI). Mechanistically, PrP^C was up-regulated by transforming growth factor-β1-suppressor of mothers against decapentaplegic 3 signaling. PrP^C activated TANK binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) signaling through its capacity for liquid-liquid phase separation, which promoted a profibrotic response in PTECs and fibroblasts. Treating mice with amlexanox, a US Food and Drug Administration-approved inhibitor of TBK1, either before the onset of renal fibrosis (in UUO and UIRI models) or after its establishment (in adenine- and aristolochic acid-induced CKD models), mitigated worsening of renal fibrosis and renal function. Collectively, our findings uncovered a mechanism involving phase separation of PrP^C underlying renal fibrosis and support further study of the PrP^C-TBK1-IRF3 axis as a potential therapeutic target for CKD.