Effect of Fumarate on Nuclear Factor Erythroid 2 and Transforming Growth Factorβ1 Signaling in Doxorubicin-Induced Cardiorenal Injury.
Osaze Edosuyi1*, Owolabi Olusola Ajiboye1, Zainab Olawunmi Lawal1, Ayomide Peace Adeyeye2, Ilekhuoba Osazee Eric2, Ojeagbase Choice Ohiakhueche2, Vashti Edosuyi3, Edo-Izevbizua Osazee Emmanuel2, Aladuna Joseph Omo-Erhabor2, Ighodaro Igbe1.
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Benin PMB 1154,
Benin City, Nigeria. - Department of Medical Laboratory Science, School of Basic Medical Sciences, College of Medical
Sciences, University of Benin, Nigeria. - Department of Child Health, University of Benin Teaching Hospital, Benin City, Nigeria,
| Key words:
Nuclear factor erythroid 2-related factor 2, transforming growth factorβ1, cardiorenal, doxorubicin, cardiorenal injury.
*Corresponding Author: osaze.edosuyi@uniben.edu
Page No: 87–94
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AbstractNuclear factor erythroid 2-related factor 2 (NRF2) and transforming growth factor (TGFβ1) signalling have been recently implicated in doxorubicin (dox)-induced cardiorenal injury. This study investigated the role of NRF2 and TGFβ1 in mediating the actions of fumarate, a tricarboxylic acid cycle metabolite, in dox-induced cardiorenal injury. Male Wistar rats were grouped into I: control (distilled water, 3 ml/kg, po), II: dox (10 mg/kg, ip), III: dox (10 mg/kg, ip) + fumarate (50 mg/kg, po) and IV: dox (10 mg/kg, ip) + fumarate (100 mg/kg). Treatments lasted for seven days, followed by euthanasia. Blood was withdrawn and the heart and kidneys were excised for biochemical and molecular assays. NRF2 expression in the heart was increased in the dox group (145.8±1.3 vs 150.8±0.4. P < 0.05) vs control. Fumarate exerted peak reduction at 50 mg/kg (150.8±0.4 vs 115.6±1.9, P < 0.001), in dox-treated animals. Fumarate increased the expression of TGFβ1 in the kidneys of dox-treated animals at 50 mg/kg (78.6±0.5 vs 82.2±0.42, P < 0.001) but reversed the decrease in the expression of NRF2 (29.7±0.2 vs 33.0±0.2, P < 0.001) at 50 mg/kg and (29.7±0.2 vs 31.3±0.3, P < 0.05) at 100 mg/kg. Aspartate transaminase (AST) and alanine transaminase (ALT) levels were increased, and fumarate reduced the expression of these enzymes in dox-treated animals. There was an adverse increase in chloride and lipoprotein levels at 100 mg/kg of fumarate (P < 0.05) in dox-treated animals. Data showed that fumarate evoked a cardio-renoprotective effect via selective modulation of NRF2 and TGFβ1 signaling in dox-induced injury.
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