Bardoxolone ameliorates TGF-β1-associated renal fibrosis through Nrf2/Smad7 elevation

Min Kyun Song, Jin Hee Lee, In geun Ryoo, Sang hwan Lee, Sae Kwang Ku, Mi Kyoung Kwak

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72 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) is a potent pathogenic factor of renal injury through the upregulation of extracellular matrix (ECM) expression and facilitation of renal fibrosis. Nuclear factor erythroid 2-like 2 (Nfe2l2; Nrf2), a master regulator of antioxidant and detoxifying systems, is mainly controlled by the binding with cytosolic protein Kelch-like ECH-associated protein 1 (Keap1) and subsequent proteasomal degradation. The protective effect of Nrf2 on renal injury has been attributed to its antioxidant role, where it aids in coping with oxidative stress-associated progression of renal disease. In this study, we investigated the effect of Nrf2 activation on ECM production and TGF-β/Smad signaling using Keap1-silenced MES-13 cells (a genetic glomerular mesangial cell model with Nrf2 overexpression). The TGF-β1-inducible expression of fibronectin and α-smooth muscle actin (α-Sma) was suppressed and Smad2/3 phosphorylation was blocked in Nrf2-high mesangial cells as compared with that in control cells. Notably, in these Nrf2-high mesangial cells, levels of TGF-β1 receptor 1 (TβR1) were substantially diminished, and the protein levels of Smad7, an inhibitor TGF-β1/Smad signaling, were increased. Nrf2-mediated Smad7 elevation and its anti-fibrotic role in Keap1-silenced cells were confirmed by studies with Nrf2-or Smad7-silencing. As a molecular link for Smad7 elevation in Nrf2-high cells, the reduction of Smad-ubiquitination-regulatory factor 1 (Smurf1), an E3 ubiquitin ligase for Smad7, was notable. Silencing of Smurf1 increased Smad7 in the control mesangial cells; however, forced expression of Smurf1 repressed Smad7 levels in Keap1-silenced cells. Additionally, we demonstrate that bardoxolone (BARD; CDDO-methyl), a pharmacological activator of Nrf2, increased Smad7 levels and attenuated TGF-β/Smad/ECM expression in MES-13. Moreover, in an aristolochic acid (AA)-mediated nephropathy mouse model, the renal expression of Nrf2 and Smad7 was elevated by BARD treatment, and AA-induced tubular necrosis and interstitial fibrosis were substantially ameliorated by BARD. Collectively, these results indicate that the Nrf2-Smad7 axis plays a key role in the protection of TGF-β-induced renal fibrosis, and further suggest a novel molecular mechanism of beneficial effect of BARD on renal disease.

Original languageEnglish
Pages (from-to)33-42
Number of pages10
JournalFree Radical Biology and Medicine
Volume138
DOIs
StatePublished - Jul 2019

Bibliographical note

Funding Information:
This study was financially supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korea government (NRF-2013M3A9B5075839, NRF-2015R1A2A1A10054384, and 2018R1A2A1A05078894). This study was also supported by the BK21Plus grant of NRF funded by the Korean government (22A20130012250) and by the Catholic University of Korea, Research Fund 2018.

Funding Information:
This study was financially supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korea government ( NRF-2013M3A9B5075839 , NRF-2015R1A2A1A10054384 , and 2018R1A2A1A05078894 ). This study was also supported by the BK21Plus grant of NRF funded by the Korean government ( 22A20130012250 ) and by the Catholic University of Korea , Research Fund 2018.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • Bardoxolone methyl (BARD)
  • Glomerular mesangial cells
  • Nfe2l2/Nrf2
  • Renal fibrosis
  • Smad7
  • TGF-β

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