Renal fibrosis is a common pathological characteristic of chronic kidney disease (CKD) and serves as the critical prognostic indicator for renal outcomes. However, current therapeutic strategies for managing renal fibrosis remain limited. Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2), an evolutionarily conserved kinase, is implicated in cell proliferation and apoptosis in various pathological contexts. However, its role in renal fibrosis is unclear. The expression of DYRK2 and association with renal injury and fibrosis were assessed in pathological sections from various CKD subtypes. Two independent renal fibrosis models, namely unilateral ureteral obstruction-induced and aristolochic acid-induced mice, were used to investigate the role of DYRK2 in renal fibrosis. Integrated multi-omics approaches, including RNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC–MS/MS) interactomics, were employed to elucidate the underlying mechanisms. Clinically, DYRK2 expression was elevated in patients with CKD and strongly correlated with histopathological fibrosis, glomerular filtration rate (GFR) decline, and an increased urine albumin-to-creatine ratio (UACR) in patients. In experimental fibrosis models, DYRK2 expression was markedly upregulated, which was particularly observed in proximal tubules. Silencing DYRK2 attenuated tubular injury, collagen deposition, and fibroblast activation. RNA sequencing revealed significant enrichment of oxidative stress-related pathways upon DYRK2 silencing. Functional studies demonstrated that DYRK2 ablation restored redox homeostasis in renal tubular epithelial cells (RTECs). Moreover, Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment showed that DYRK2 ablation restored the G2/M phase of the cell cycle in RTECs, reflected by a decrease in the cyclin B1/cyclin D1 ratio, as well as reduced levels of p21 and phosphorylated histone H3 (P-H3). Mechanistically, mass spectrometry screening and co-immunoprecipitation assays revealed an interaction of DYRK2 and cyclin-dependent kinase 1 (CDK1). Notably, DYRK2 promoted phosphorylation of CDK1 at the Thr14 site, thereby inhibiting its activity. The increased Thr14 phosphorylation of CDK1 almost reversed the protective effects of DYRK2 loss on transforming growth factor (TGF)-β1-induced tubular cell injury and fibrosis. These findings highlight the pivotal role of DYRK2 in driving G2/M dysregulation in RTECs under fibrotic conditions. Targeting DYRK2 may offer a promising and novel therapeutic strategy for renal fibrosis.
Bai et al. (Fri,) studied this question.