Chymase Inhibition Attenuates Kidney Fibrosis in a Chronic Mouse Model of Renal Ischemia–Reperfusion Injury

TL;DR

Inhibiting chymase reduces kidney fibrosis in mice with chronic renal injury, suggesting a potential treatment for preventing chronic kidney disease after acute injury.

Contribution

This study demonstrates that chymase inhibition can attenuate renal fibrosis in a chronic mouse model of ischemia-reperfusion injury.

Findings

TY-51469, a chymase inhibitor, significantly suppressed fibrosis formation in I/R-injured kidneys.

Chymase inhibition reduced TGF-β1 expression and collagen I levels in injured kidneys.

Fibrosis was most pronounced in the cortex-medulla transition region in placebo-treated mice.

Abstract

Although various factors contribute to the transition from acute kidney injury (AKI) to chronic kidney disease (CKD), no clinically effective pharmacological treatment has been established. We investigated whether chymase inhibition is effective in preventing renal fibrosis, a key process in the transition from AKI to CKD. Male BALB/c mice were subjected to unilateral ischemia-reperfusion (I/R) injury, and TY-51469, a chymase-specific inhibitor, was administered intraperitoneally at a dose of 10 mg/kg/day for 6 weeks. The 45 min ischemic period followed by 6 weeks of reperfusion resulted in severe renal atrophy. Renal fibrosis was particularly pronounced in the transition region between the cortex and medulla in placebo-treated mice. The expression of mouse mast cell protease 4 (MMCP-4, a mouse chymase) mRNA, the number of chymase-positive mast cells, and fibrosis-related factors, such as transforming growth factor (TGF)-β1 and collagen I, were all significantly increased in I/R-injured kidneys. However, treatment with TY-51469 significantly suppressed fibrosis formation, along with the inhibition of renal chymase and TGF-β1 expression. These findings suggest that chymase inhibition may be a potential therapeutic strategy for preventing the transition from AKI to CKD by reducing fibrosis.

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