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Updated: May 12, 2025
Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice
Published on: August 9, 2013
Chymase Inhibition Attenuates Kidney Fibrosis in a Chronic Mouse Model of Renal Ischemia-Reperfusion Injury
Sakura Kure1,2, Hiroe Toba3,4, Denan Jin1,4
1Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan.
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.
Insights
Chymase inhibition effectively reduced renal fibrosis following acute kidney injury (AKI) in mice. This suggests chymase inhibitors could prevent the progression from AKI to chronic kidney disease (CKD).
Area of Science:
- Nephrology
- Pharmacology
- Fibrosis Research
Background:
- The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) lacks effective pharmacological treatments.
- Renal fibrosis is a critical pathological process in AKI-to-CKD progression.
Purpose of the Study:
- To investigate the efficacy of chymase inhibition in preventing renal fibrosis after AKI.
- To explore TY-51469, a chymase-specific inhibitor, as a potential therapeutic strategy.
Main Methods:
- Male BALB/c mice underwent unilateral ischemia-reperfusion (I/R) injury.
- Mice received TY-51469 (10 mg/kg/day) or placebo for 6 weeks post-injury.
- Assessed renal atrophy, fibrosis, chymase expression (MMCP-4), mast cell counts, and fibrosis markers (TGF-β1, collagen I).
Main Results:
- I/R injury led to severe renal atrophy and pronounced fibrosis, particularly in placebo-treated mice.
- Increased expression of MMCP-4, chymase-positive mast cells, TGF-β1, and collagen I was observed in injured kidneys.
- TY-51469 treatment significantly suppressed fibrosis, renal chymase, and TGF-β1 expression.
Conclusions:
- Chymase plays a significant role in the development of renal fibrosis post-AKI.
- Chymase inhibition with TY-51469 demonstrates potential for preventing AKI-to-CKD transition by mitigating fibrosis.
- Targeting chymase represents a promising therapeutic avenue for managing kidney injury progression.
