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.

Regression of Renal Disease by Angiotensin II Antagonism Is Caused by Regeneration of Kidney Vasculature

“…16 Such pathways can be theoretically targeted therapeutically to counteract the effects of oxidative stress and TGF-b/Smad-mediated renal fibrosis. [17][18][19][20] Finding here that RAS blockade rescues Nrf2 expression (as shown in Figure 4C), which was significantly decreased in untreated MWF rats, is consistent with this possibility.…”

Role of Nrf2 Signaling in the Regulation of Vascular BK Channel β1 Subunit Expression and BK Channel Function in High-Fat Diet–Induced Diabetic Mice

“…These animals were fed with a 60% fat diet (HFD) or 10% fat diet (low-fat diet [LFD]) for 6 months. In the dimethyl fumarate (DMF) treatment studies, after 6 months eating an HFD or LFD animals were randomly divided into four groups (DMF-treated LFD, placebo-treated LFD, DMF-treated HFD, and placebo-treated HFD) and were treated with DMF (25 mg/kg/daily) or placebo (same volume of vehicle) by gavage for 10 days (28,29). Tail blood pressures were measured using a CODA Non-Invasive Blood Pressure System (Kent Scientific Corporation, Torrington, CT), and blood glucose levels were determined using an Accu-CHEK Aviva Glucose Meter (Roche Diabetes Care Inc., Indianapolis, IN).…”

Microparticulate/nanoparticulate powders of a novel Nrf2 activator and an aerosol performance enhancer for pulmonary delivery targeting the lung Nrf2/Keap-1 pathway

“…Recently, the DMF was approved in the United States as an orally administered delayed-release capsule, Tecfidera ® (Biogen, Research Triangle Park, NC) to treat the autoimmune neurological disease, multiple sclerosis. The approval of DMF to treat multiple sclerosis has opened doors to new avenues for research in using the DMF in other inflammatory and autoimmune conditions, such as polyarthiritis, vascular calcification 19 , renal fibrosis 20 , and pancreatitis 21, 22 .…”