CH6824025, potent and selective DDR1 inhibitor, reduces kidney fibrosis in UUO mice
Discoidin domain receptor 1 (DDR1) is a collagen receptor with tyrosine kinase activity, and its expression is enhanced in various disease conditions. Although previous research suggests that DDR1 contributes to renal disease progression, DDR1 inhibitors for renal fibrosis have yet to be developed. In this study, we used unilateral ureteral obstruction (UUO) mice to investigate whether CH6824025, a strong and selective DDR1 phosphorylation inhibitor, can improve renal fibrosis. Furthermore, to analyze its action in detail, we performed 10x Visium spatial transcriptomics (ST) analysis on the kidney. Orally administered CH6824025 suppressed the phosphorylation of DDR1 in renal tissue, and the amount of hydroxyproline, the Sirius red-positive area, and the mRNA expression of fibrosis and inflammation-related genes in the kidney were significantly decreased. 10x Visium ST analysis suggested that DDR1 is mainly expressed in distal nephrons under normal conditions, but that its expression appears to increase in the injured proximal tubules in UUO mice. Comparing mRNA expression in DDR1 positive spots in the vehicle and the CH6824025 administration group, oxidative phosphorylation and mitochondrial dysfunction were improved, and pathways involved in fibrosis inhibited in the CH6824025 administration group. Downstream analysis suggested that mRNA expression changes in the CH6824025 administration group contribute to the inhibition of cell movement. Taken together, our findings suggest that CH6824025 inhibited the migration of inflammatory cells to the injury site in UUO mice, reduced inflammation, and brought about the maintenance of cell homeostasis and inhibition of fibrosis. DDR1 inhibitors are expected to be a promising treatment for renal fibrosis. Overall design: After the allocation of mice, the oral once daily administration of vehicle or CH6824025 was started. Seven days after the surgery of UUO, mice were subjected to analysis. FFPE blocks of kidneys from each group (Sham n=1, UUO Vehicle group n=3, UUO CH6824025 200 mg/kg group n=4) were used.