Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling.
TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta 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 (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, DMF and Ad-Nrf2 repressed TGF-beta-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-beta-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 alpha-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-beta/Smad3 signaling in an ARE-independent manner, suggesting that DMF could be used to treat renal fibrosis.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-Y CHEMICAL GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-N GENE-N GENE-Y GENE-N GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
DMF DMF DMF Dimethylfumarate TGF-beta NQO1 HO-1 glutathione S-transferase GST TGF-beta glutathione ARE alpha-SMA fibronectin type 1 collagen Nrf2 phospho-Smad3 Nrf2 TGF-beta Smad3 ARE S Nrf2 TGF-beta Nrf2 Nrf2 TGF-beta Nrf2 Nrf2 Nrf2 PAI-1 alpha-smooth muscle actin DMF alpha-SMA fibronectin type 1 collagen TGF-beta Nrf2 TGF-beta Smad3 TGF-beta Smad3 Nrf2 DMF antioxidant response element ARE Nrf2 Smad NF-E2-related factor 2 transforming growth factor-beta DMF DMF DMF dimethylfumarate DMF