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Therapeutic effect of Y-27632 on chronic allograft nephropathy in rats
Background:
Chronic allograft nephropathy (CAN) is a major cause of late allograft loss. Recent evidences suggest that Rho and its downstream effector ROCK may be greatly involved in the progression of renal fibrosis. Inhibition of Rho/ROCK pathway might interact with the inflammatory process in the renal interstitium, and antagonize the process of epithelial-to-mesenchymal transition (EMT). We hypothesized that Y-27632 could inhibit the chronic inflammatory process and prevent the progression of CAN.
Materials And Methods:
Fisher (F344) kidneys were orthotopically transplanted into Lewis rat recipients. Lewis to Lewis rat kidney transplantation was served as the syngeneic control (Syn group). Allograft recipients were randomized and treated with either cyclosporine A alone (Allo group), or in combination with Y-27632 (30 mg/kg body weight/d intragastric, Y-27632 group). Renal function and urine protein excretion levels of the rats were analyzed. Animals were sacrificed 12 wk post-transplantation for histological and immunohistochemical studies, as well as analysis of the expression levels of chemokines, transforming growth factor (TGF-beta) 1 and alpha smooth muscle actin (alpha-SMA).
Results:
Renal function deteriorated progressively in the Allo group, and there was typical CAN morphology in the kidneys. However, Y-27632-treatment significantly prevented the deterioration of graft function, lessened the level of urine protein excretion, and preserved the renal structure. Attenuation of ED1 positive mononuclear cell infiltration and amelioration of tubulointerstitial fibrosis were achieved by Y-27632 intervention. This was associated with down-regulation of the expression of tubular monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and phosphorylated NF-kappaB (which was a marker for activation). Profibrotic protein (TGF-beta1) and alpha-SMA, a marker of EMT, were significantly down-regulated by Y-27632 treatment as well.
Conclusions:
The Rho/ROCK pathway plays an important role in the progression of CAN, and specific inhibition of Rho activity by Y-27632 showed favorable effects on blocking renal interstitial inflammation and fibrosis, thus efficiently retarding the development of CAN, which might provide us with a novel strategy to improve long-term renal graft survival.
Insights
Y-27632, a Rho-kinase inhibitor, effectively reduced inflammation and fibrosis in chronic allograft nephropathy (CAN) in rats. This intervention improved kidney function and may offer a new strategy for enhancing long-term renal graft survival.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Chronic allograft nephropathy (CAN) is a primary cause of late kidney transplant failure.
- The Rho/ROCK pathway is implicated in renal fibrosis and epithelial-to-mesenchymal transition (EMT).
- Inhibiting the Rho/ROCK pathway may counteract renal inflammation and fibrosis.
Purpose of the Study:
- To investigate the potential of Y-27632, a Rho-kinase inhibitor, in preventing chronic allograft nephropathy (CAN).
- To evaluate the effects of Y-27632 on renal inflammation, fibrosis, and graft function in a rat kidney transplant model.
Main Methods:
- Orthotopic kidney transplantation performed in Fisher (F344) to Lewis rats, with Lewis to Lewis as syngeneic control.
- Allograft recipients treated with cyclosporine A alone or in combination with Y-27632.
- Assessment of renal function, urine protein, histology, immunohistochemistry, and molecular markers (chemokines, TGF-β1, α-SMA) at 12 weeks post-transplantation.
Main Results:
- Y-27632 treatment significantly preserved renal function and reduced proteinuria compared to controls.
- Histological analysis revealed attenuated interstitial fibrosis and reduced inflammatory cell infiltration in Y-27632 treated rats.
- Down-regulation of pro-inflammatory markers (MCP-1, RANTES, p-NF-κB) and fibrotic markers (TGF-β1, α-SMA) was observed with Y-27632 treatment.
Conclusions:
- The Rho/ROCK pathway is a key contributor to the progression of CAN.
- Specific inhibition of Rho activity with Y-27632 demonstrates protective effects against renal interstitial inflammation and fibrosis.
- Y-27632 represents a potential therapeutic strategy to improve long-term renal allograft survival.