NFE2L2 (Nrf2) attenuates Tgf‐β1 signaling by elevation of Smad7 in mouse mesangial MES‐13 cells

Abstract

Renal fibrosis is the principal process underlying the progression of kidney diseases. Accumulating evidence indicates that oxidative stress plays a crucial role in renal fibrotic diseases. Transforming growth factor‐β1 (Tgf‐β1) is a potent stimulator of profibrotic responses, including expression of fibrosis markers such as extracellular matrix (ECM) and α‐smooth muscle actin (α‐SMA) through a Smad‐dependent pathway. Therefore, Smad‐dependent Tgf‐β1 signaling is known to play pivotal roles in renal fibrosis. In this regard, we investigated the potential involvement of nuclear factor (erythroid‐derived 2)‐like 2 (NFE2L2; Nrf2) in renal fibrosis with Tgf‐β1–Smad signaling. We previously reported that Smad7, a negative regulator of Smad signaling, may be a linker molecule between the Nrf2 pathway and Tgf‐β1 signaling in human renal tubular epithelial HK2 cell. In this study, we confirmed that elevated protein level of Smad7 attenuates Tgf‐β1 signaling by degradation of Tgf‐β1 Receptor 1 (TβR1) in Kelch‐like ECH‐associated protein 1 (Keap1) knockdown mouse mesangial MES‐13 cell, a cellular model of Nrf2 overexpression. As one of potential underlying molecular mechanisms of Smad7 regulation by Nrf2, reduced level of Smad‐ubiquitination‐regulatory factor 1 (Smurf1), an E3 ubiquitin ligase for Smad7, was remarkable. Further, we demonstrated that a Nrf2 inducer bardoxolone methyl ester (BARD), which is on clinical trials for kidney diseases, also elevated Smad7 level and attenuated Tgf‐β1 signaling in MES‐13. Collectively, these results indicate that Nrf2 can be an effective inhibitor of Smad‐dependent Tgf‐β1 signaling, and imply the beneficial role of Nrf2 in renal fibrosis.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF‐2015R1A2A1A10054384)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.