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Updated: Oct 1, 2026
Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
Published on: April 25, 2025
Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction
Katsuyuki Nagatoya1, Toshiki Moriyama, Noritaka Kawada
1Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, and School ofHealth and Sport Sciences, Osaka University, Osaka, Japan.
Background:
The small GTPase Rho is involved in cell-to-substratum adhesion and cell contraction. These actions of Rho mediated by downstream Rho effectors such as Rho-associated coiled-coil forming protein kinase (ROCK) may be partly responsible for the progression of renal interstitial fibrosis.
Methods:
The anti-fibrosis effects of Y-27632, a specific ROCK inhibitor, were studied both in vivo (unilateral ureteral obstruction; UUO) and in vitro. To investigate the therapeutic efficacy of Y-27632 in UUO kidneys, smooth muscle alpha actin (SMalphaA) expression, macrophage infiltration and fibrosis in the obstructed kidneys were studied. SMalphaA, transforming growth factor beta (TGF-beta), alpha1 (I) collagen, osteopontin, macrophage chemoattractant peptide-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) gene expression were examined by Northern blotting. To elucidate the mechanism linking the Rho-ROCK pathway with renal fibrosis, the effects of Y-27632 on in vitro cell proliferation and cell migration were studied.
Results:
In vivo analysis showed that Y-27632 suppressed SMalphaA expression, macrophage infiltration and interstitial fibrosis, and that Y-27632 suppressed SMalphaA, TGF-beta and alpha1 (I) collagen mRNA expression. In vitro analysis showed that Y-27632 did not suppress proliferation of renal fibroblasts but suppressed migration of macrophages.
Conclusions:
The Rho-ROCK system may play an important role in the development of tissue fibrosis, and the Rho-ROCK signaling pathway may be a new therapeutic target for preventing interstitial fibrosis in progressive renal disease.
Insights
The Rho-associated coiled-coil forming protein kinase (ROCK) pathway contributes to renal interstitial fibrosis. Inhibiting ROCK with Y-27632 reduced fibrosis and macrophage migration in obstructed kidneys, suggesting a therapeutic target.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- The small GTPase Rho and its effector Rho-associated coiled-coil forming protein kinase (ROCK) are implicated in cell adhesion and contraction.
- These Rho-mediated actions may contribute to the progression of renal interstitial fibrosis.
Purpose of the Study:
- To investigate the anti-fibrosis effects of Y-27632, a specific ROCK inhibitor, in a preclinical model of renal interstitial fibrosis.
- To elucidate the role of the Rho-ROCK pathway in renal fibrosis development and progression.
Main Methods:
- In vivo study using unilateral ureteral obstruction (UUO) model in rodents.
- In vitro studies assessing fibroblast proliferation and macrophage migration.
- Analysis of gene expression for markers of fibrosis, inflammation, and adhesion molecules (SMalphaA, TGF-beta, alpha1(I) collagen, osteopontin, MCP-1, ICAM-1).
Main Results:
- Y-27632 treatment significantly suppressed smooth muscle alpha actin (SMalphaA) expression, macrophage infiltration, and interstitial fibrosis in UUO kidneys.
- Y-27632 inhibited mRNA expression of SMalphaA, transforming growth factor beta (TGF-beta), and alpha1 (I) collagen.
- In vitro, Y-27632 did not affect renal fibroblast proliferation but inhibited macrophage migration.
Conclusions:
- The Rho-ROCK signaling pathway plays a significant role in the development of renal interstitial fibrosis.
- Targeting the Rho-ROCK pathway with inhibitors like Y-27632 represents a potential therapeutic strategy for preventing progressive renal disease and fibrosis.
