Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling.

Abstract

TGF-β plays a key role in the development of renal fibrosis. Suppressing the TGF-β signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-β signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-β signaling. Results showed that DMF increased nuclear levels of Nrf2, and both DMF and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (α-SMA), fibronectin and type 1 collagen expression in TGF-β-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, DMF and Ad-Nrf2 repressed TGF-β-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of DMF on TGF-β-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of DMF. Finally, DMF suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and α-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, DMF attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-β/Smad3 signaling in an ARE-independent manner, suggesting that DMF could be used to treat renal fibrosis.

• Authors: Chang Joo Oh, Joon-Young Kim, Young-Keun Choi, Han-Jong Kim, Ji-Yun Jeong, Kwi-Hyun Bae, Keun-Gyu Park, In-Kyu Lee
• Journal: PloS one (PLoS One) Vol. 7 Issue 10 Pg. e45870 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23056222 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Collagen Type I
• Fibronectins
• Fumarates
• Immunosuppressive Agents
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Plasminogen Activator Inhibitor 1
• Smad3 Protein
• Transforming Growth Factor beta
• Dimethyl Fumarate

Topics

• Actins (genetics, metabolism)
• Animals
• Blotting, Western
• Cell Line
• Collagen Type I (genetics, metabolism)
• Dimethyl Fumarate
• Fibronectins (genetics, metabolism)
• Fibrosis
• Fumarates (pharmacology)
• HEK293 Cells
• Humans
• Immunosuppressive Agents (pharmacology)
• Kidney (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Muscle, Smooth (metabolism)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Phosphorylation (drug effects)
• Plasminogen Activator Inhibitor 1 (genetics, metabolism)
• RNA Interference
• Rats
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Smad3 Protein (genetics, metabolism)
• Transforming Growth Factor beta (pharmacology)