POS-385 CXCR2 Plays a Role in Promoting Renal Fibrosis by Accelerating Tubular Cell Senescence

Abstract

Renal fibrosis is the common pathologic feature for all kinds of chronic kidney diseases (CKD). The premature aging in renal tubular cells plays an important role in the progression of renal fibrosis. However, the underlying mechanisms of tubular senescence have not been elucidated. In this study, we explored the role of CXCR2 in tubular senescence. The expression of CXCR2 in the kidneys of various CKD animal models was assessed. Mitochondrial function, tubular cellular senescence, and renal fibrosis were analyzed in CXCR2-overexpressed or IL-8, a CXCR2 ligand-treated CKD mice and tubular cells. A siRNA strategy or specific inhibitor to CXCR2 was also adopted. CXCR2 was highly upregulated in various CKD models, and colocalized with the senescence-related protein p16INK4A. CXCR2 expression was level intimately correlated with the extent of renal fibrosis, mitochondrial dysfunction, and p16INK4A expression. Furthermore, ectopic expression of CXCR2 in unilateral ischemia-reperfusion injury (UIRI) and unilateral ureteral obstruction (UUO) induced further damage of mitochondrial function and exacerbated renal fibrosis. Activation of CXCR2 via the ligand, IL-8 binding exacerbated tubular senescence, and mitochondrial dysfunction which were evidenced by decrease in mitochondrial biogenesis-related transcription factors peroxisome proliferator-activated receptor-coactivator-1α (PGC-1α) and transcription factor A, mitochondrial (TFAM), increase in p16INK4Aexpression and senescence-associated β-galactosidase (SA-β-gal) activity in vivo and vitro. Conversely, SB225002, a specific inhibitor of CXCR2, repressed UUO-induced renal fibrosis and impeded senescence in cultured tubular epithelial cells. In UIRI mice, CXCR2-accelerated renal fibrosis was inhibited by shRNA-mediated silencing of p16INK4A. Overexpression of CXCR2 remarkably downregulated expressional levels of PGC-1α and TFAM, but upregulated levels of senescence-related p16INK4A and γH2AX, and promoted fibrosis-related morphology changes in tubular cells. Thus, CXCR2 drives renal fibrosis through inducing tubular senescence. The underlying mechanism is related to its regulation on mitochondrial dynamic. Although the more specific signaling mechanisms need to be clarified, our study still provides an important clue showing CXCR2 as a potential target for the prevention and treatment of CKD.