Effects of Chymase Inhibition on Chronic Renal Injury Following Bilateral Ischemia-Reperfusion in Mice

Background: Ischemia–reperfusion (I/R) injury is a major risk factor for the development of chronic kidney disease (CKD). However, effective treatments for preventing CKD progression following I/R injury have not yet been established. Methods: Mice underwent bilateral renal I/R injury and received continuous treatment with TY51469, a chymase-specific inhibitor. Renal injury and fibrosis were as-sessed six weeks after I/R. Blood urea nitrogen (BUN) levels, renal collagen deposition, mast cell ac-cumulation, mouse mast cell protease-4 (MMCP-4) expression, and the expression of fibrosis- and in-flammation-related genes were evaluated. Correlations between MMCP-4 and fibrosis- and inflamma-tion-related gene expression were also analyzed. Results: Six weeks after I/R injury, mice exhibited elevated BUN levels, increased renal collagen deposition, and upregulated expression of fibrosis- and inflammation-related genes, including transforming growth factor-beta 1 (TGF-β1), collagen I, matrix metalloproteinase-9 (MMP-9), and tumor necrosis factor-alpha (TNF-α). Mast cell accumulation and MMCP-4 expression were also markedly increased, particularly in fibrotic regions. Continuous treat-ment with TY51469 significantly attenuated BUN elevation, renal fibrosis, mast cell accumulation, MMCP-4 expression, and the upregulation of fibrosis- and inflammation-related genes. Furthermore, MMCP-4 expression was strongly positively correlated with the expression of TGF-β1, collagen I, MMP-9, and TNF-α. Conclusions: These findings suggest that mast cell-derived chymase contributes to renal fibrotic progression following I/R injury and that chymase inhibition may represent a poten-tial therapeutic strategy for preventing CKD development.