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Nrf2 and Snail-1 in the prevention of experimental liver fibrosis by caffeine
Daniela Gordillo-Bastidas1, Edén Oceguera-Contreras1, Adriana Salazar-Montes1
1Daniela Gordillo-Bastidas, Edén Oceguera-Contreras, Adriana Salazar-Montes, Jaime González-Cuevas, Luis Daniel Hernández-Ortega, Juan Armendáriz-Borunda, Institute of Molecular Biology in Medicine and Gene Therapy/CUCS, University of Guadalajara, Guadalajara, Jalisco 44100, México.
Aim:
To determine the molecular mechanisms involved in experimental hepatic fibrosis prevention by caffeine (CFA).
Methods:
Liver fibrosis was induced in Wistar rats by intraperitoneal thioacetamide or bile duct ligation and they were concomitantly treated with CFA (15 mg/kg per day). Fibrosis and inflammatory cell infiltrate were evaluated and classified by Knodell index. Inflammatory infiltrate was quantified by immunohistochemistry (anti-CD11b). Gene expression was analyzed by quantitative reverse transcription-polymerase chain reaction for collagen I (Col-1), connective tissue growth factor (CTGF), transforming growth factor β1 (TGF-β1), tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-6, superoxide dismutase (SOD) and catalase (CAT). Activation of Nrf2 and Snail-1 was analyzed by Western-blot. TNF-α expression was proved by enzyme-linked immunosorbant assay, CAT activity was performed by zymography.
Results:
CFA treatment diminished fibrosis index in treated animals. The Knodell index showed both lower fibrosis and necroinflammation. Expression of profibrogenic genes CTGF, Col-1 and TGF-β1 and proinflammatory genes TNF-α, IL-6 and IL-1 was substantially diminished with CFA treatment with less CD11b positive areas. Significantly lower values of transcriptional factor Snail-1 were detected in CFA treated rats compared with cirrhotic rats without treatment; in contrast Nrf2 was increased in the presence of CFA. Expression of SOD and CAT was greater in animals treated with CFA showing a strong correlation between mRNA expression and enzyme activity.
Conclusion:
Our results suggest that CFA inhibits the transcriptional factor Snail-1, down-regulating profibrogenic genes, and activates Nrf2 inducing antioxidant enzymes system, preventing inflammation and fibrosis.
