Abstract
Renal fibrosis is the common pathological feature of various chronic kidney diseases (CKD). Tubular cell senescence plays a key role in the progression of renal fibrosis. However, the underlying mechanisms are still in mystery. In this study, we identified, Pentraxin 3 (PTX3), belonging to the Pentraxin family, is a new fibrogenic factor. PTX3 was increased in various CKD models. PTX3 was primarily localized in tubular epithelial cells and upregulated, accompanied by mitochondrial dysfunction and cellular senescence. Overexpression of PTX3 aggravated mitochondrial damage and accelerated cell senescence in tubular cells, leading to more severe fibrogenesis in kidneys. However, knockout of PTX3 significantly preserved mitochondrial homeostasis, and blocked cellular senescence in primary cultured tubular cells. Furthermore, KYA1797K, a destabilizer of β-catenin, greatly inhibited PTX3-induced mitochondrial dysfunction, tubular cell senescence, and renal fibrosis. Overexpression of PTX3 triggered nuclear translocation of β-catenin, an activating form of β-catenin. PTX3-induced mitochondrial dysfunction and tubular cell senescence were also significantly inhibited by knockdown of p16INK4A, a senescence-related protein. In a clinical cohort, we found PTX3 was increased in urine and serum in patients with CKD. Urinary PTX3 negatively correlated with eGFR. PTX3 also increased gradually following the severity of diseases, triggering the fibrogenesis. Taken together, our results provide strong evidences that PTX3 is a new fibrogenic factor in the development of renal fibrosis through β-catenin-induced mitochondrial dysfunction and cell senescence. This study further suggests PTX3 is a new diagnostic factor to renal fibrosis and provides a new therapeutic target against renal fibrosis.