Suppression of iNOS/HIF-1α/MMP-9/α-SMA/collagen Axis of Fibrosis and Systemic Hypertension in Thioacetamide-induced Liver Injury by Resveratrol

Abstract Chronic liver injury can lead to hepatic failure and the only available method of treatment would be liver transplantation. The link between nitrosative stress (iNOS), hypoxia-inducible factor-1α (HIF-1α), and alpha-smooth muscle actin (α-SMA), in thioacetamide (TAA)-induced liver fibrosis and hypertension in treatment with the anti-inflammatory and antioxidant, resveratrol (RES) was not investigated before. Consequently, we injected rats with either 200 mg/kg TAA for 8 weeks starting at week 2 (model group) or pretreated them before TAA injections with RES (20mg/kg) for two weeks and continued on RES and TAA until being culled at week 10 (protective group). In the model group, we documented the induction of hepatic fibrosis and upregulation of tissue iNOS, HIF-1α, and the pro-fibrotic biomarkers α-SMA and matrix metalloproteinase-9 (MMP-9) that was significantly (p ≤ 0.0014) ameliorated by RES. RES also significantly (p ≤ 0.0232) reduced triglycerides (TG), cholesterol (CHOL), very low-density lipoprotein (vLDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) induction by TAA. Also, a significant (p<0.0001) positive correlation between iNOS/HIF-1α/α-SMA/collagen axis and hypertension and liver injury biomarkers was observed. These findings indicate that the hepatotoxic compound, TAA augments iNOS/HIF-1α/MMP-9/α-SMA/collagen mediated fibrosis and hypertension, and is inhibited by RES for 10 weeks.