Fasudil alleviates hepatic fibrosis in type 1 diabetic rats: involvement of the inflammation and RhoA/ROCK pathway

Y. Xie, T. Song, M. Huo, Y. Zhang, Y.-Y. Zhang, Z.-H. Ma, N. Wang, J.-P. Zhang, L. Chu

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China. chuli0614@126.com

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• Pharmacology

OBJECTIVE: Rho-associated kinases (ROCKs) are recognized to be involved in many pathophysiological processes caused by hyperglycemia. We performed experiments to evaluate the effects of fasudil, the Rho/ROCK inhibitor, on preventing hepatic fibrosis in type 1 diabetic rats and to elucidate the underlying mechanisms.

MATERIALS AND METHODS: Sprague-Dawley (SD) rats were randomly divided into five groups: normal control (NC), untreated diabetic (DM), low-dose fasudil-treated (L-Fas), high-dose fasudil-treated (H-Fas) and captopril-treated (Cap) groups. Streptozotocin was injected to establish the diabetes model. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were analyzed. Hematoxylin and eosin (HE) and Masson’s trichrome staining were used for histological observations. The expression of transforming growth factor-β (TGF-β1), metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1), collagen type Iα (Coll α1), nuclear factor-kappa B (NF-κB) and ROCK-1 were measured to investigate the mechanisms involved in fibrosis.

RESULTS: The DM group exhibited hepatic fibrosis with remarkable liver damage and inflammation reaction by the activation of the NF-κB pathway. Treatment with fasudil or captopril suppressed not only the inflammation reaction but also the accumulation of the extracellular matrix due to the downregulation of TGF-β1 and MMP-9/TIMP-1, which induces the amelioration of the liver fibrosis with diabetes. Furthermore, fasudil significantly attenuated the activation of ROCK-1 and NF-κB in the livers of diabetic rats.

CONCLUSIONS: These results suggest that fasudil exert anti-inflammation actions and markedly decrease the accumulation of extracellular matrix. Fasudil is a good candidate agent for treating hepatic fibrosis in diabetes.

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