Acetylation-regulated DUSP1 deficiency contributes to renal fibrosis progression

Rationale: The irreversible damage of renal fibrosis has been widely recognized as a critical factor in the progression of chronic kidney disease (CKD) to end-stage kidney failure. This necessitates investigation into its precise mechanisms. Dual-specificity phosphatase 1 (DUSP1), a regulator of mitogen-activated protein kinase (MAPK) pathways, is linked to diseases such as cancer and immune disorders, but its role in renal fibrosis is unclear. This study aimed to clarify the role of DUSP1 in renal fibrosis, identify the intrinsic mechanisms involved, and provide a theoretical basis for the clinical translation of a new target for renal fibrosis treatment. Methods: We characterized DUSP1 expression in kidney tissues from unilateral ureteral obstruction (UUO) mice and patients with CKD using histological analysis. We established a UUO-induced renal fibrosis model using DUSP1 knockout mice. The role and mechanism of DUSP1-mediated inhibition of renal fibrosis was evaluated both in vivo and in vitro. Finally, we performed virus-mediated gene transfer, RNA-Seq, immunohistochemistry, western blotting, and qPCR to further analyze our findings. Results: We found that DUSP1, a crucial dephosphorylating enzyme, was remarkably reduced in renal tubular epithelial cells (RTECs) in mice and patients with CKD. This reduction was inversely correlated with kidney function and severity of renal fibrosis. DUSP1 deficiency exacerbated UUO-induced renal fibrosis in mice, whereas overexpression of DUSP 1 reduces fibrogenesis in human renal tubular epithelial (HK-2) cells treated with transforming growth factor-β1 in vitro. Mechanistically, deletion of DUSP1 promotes the nuclear translocation of Smad3, a crucial mediator of renal fibrosis, primarily through dephosphorylation at its 423/425 residue. Interestingly, we observed that DUSP1 is primarily regulated by acetylation modification, which is accompanied by an increased expression of histone deacetylase 1 (HDAC1) under UUO conditions. Furthermore, HDAC1 inhibition reversed the decrease in DUSP1 and the dephosphorylation of Smad3 in RTECs. Finally, the use of HDAC1 inhibitors or adeno-associated virus-mediated DUSP1 overexpression in RTECs significantly ameliorated UUO-induced renal injury and fibrosis. Conclusion: These results demonstrate that DUSP1 deficiency accelerates renal fibrosis through Smad3 nuclear translocation, modulated by HDAC1-driven acetylation. HDAC1 inhibition or DUSP1 overexpression significantly alleviated renal damage, highlighting DUSP1's therapeutic potential in combating CKD progression.