Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.
Eur Rev Med Pharmacol Sci. 2018 Sep;22(17):5665-5677. doi: 10.26355/eurrev_201809_15834.
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.
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.
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.
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.
Rho 相关激酶（ROCK）被认为参与了高血糖引起的许多病理生理过程。我们进行了实验，以评估 Rho/ROCK 抑制剂法舒地尔在预防 1 型糖尿病大鼠肝纤维化中的作用，并阐明其潜在机制。
将 Sprague-Dawley（SD）大鼠随机分为五组：正常对照组（NC）、未治疗糖尿病组（DM）、低剂量法舒地尔治疗组（L-Fas）、高剂量法舒地尔治疗组（H-Fas）和卡托普利治疗组（Cap）。链脲佐菌素注射建立糖尿病模型。分析丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）和肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）等炎症因子。苏木精和伊红（HE）和 Masson 三色染色用于组织学观察。测量转化生长因子-β（TGF-β1）、金属蛋白酶-9（MMP-9）/金属蛋白酶组织抑制剂-1（TIMP-1）、胶原 Iα（Coll α1）、核因子-κB（NF-κB）和 ROCK-1 的表达，以研究纤维化涉及的机制。
DM 组表现出肝纤维化，肝损伤和炎症反应明显，NF-κB 通路激活。法舒地尔或卡托普利的治疗不仅抑制了炎症反应，而且由于 TGF-β1 和 MMP-9/TIMP-1 的下调，抑制了细胞外基质的积累，从而改善了糖尿病引起的肝纤维化。此外，法舒地尔显著减弱了糖尿病大鼠肝脏中 ROCK-1 和 NF-κB 的激活。
这些结果表明，法舒地尔发挥抗炎作用，并显著减少细胞外基质的积累。法舒地尔是治疗糖尿病肝纤维化的一种有前途的药物。
