dimethylfumarate attenuates renal fibrosis via nf-e2-related factor 2-mediated inhibition of transforming growth factor-βsmad signaling通过nf-e2-related dimethylfumarate变弱肾纤维化因子2-mediated抑制转换增长factor-βsmad信号.pdfVIP

Dimethylfumarate Attenuates Renal Fibrosis via NF-E2- Related Factor 2-Mediated Inhibition of Transforming Growth Factor-b/Smad Signaling 1 1,2 1 1,3 1 1 Chang Joo Oh , Joon-Young Kim , Young-Keun Choi , Han-Jong Kim , Ji-Yun Jeong , Kwi-Hyun Bae , 1 1 Keun-Gyu Park , In-Kyu Lee * 1 Departments of Internal Medicine, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea, 2 GIST College, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea, 3 Research Institute of Clinical Medicine, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea Abstract TGF- b plays a key role in the development of renal fibrosis. Suppressing the TGF-b signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-b signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-b 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 (a-SMA), fibronectin and type 1 collagen expression in TGF-b-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, DMF and Ad-Nrf2 repressed TGF-b-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 suc