Nrf2 drives oxidative stress-induced autophagy in nucleus pulposus cells via a Keap1/Nrf2/p62 feedback loop to protect intervertebral disc from degeneration

被引:196
作者
Tang, Zehan [1 ]
Hu, Bo [1 ]
Zang, Fazhi [1 ]
Wang, Jianxi [1 ]
Zhang, Xingda [1 ]
Chen, Huajiang [1 ]
机构
[1] Second Mil Med Univ, Changzheng Hosp, Dept Spinal Surg, Shanghai, Peoples R China
关键词
AGE-RELATED-CHANGES; CLASSIFICATION; ACTIVATION; SENESCENCE; PATHWAY; P62;
D O I
10.1038/s41419-019-1701-3
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Intervertebral disc (IVD) degeneration is known to aggravate with age and oxidative stress is implicated in the pathogenesis of many age-related diseases. Nuclear factor (erythroid-derived-2)-like 2 (Nrf2) can confer adaptive protection against oxidative and proteotoxic stress in cells. In this study, we assessed whether Nrf2 can protect against oxidative stress in nucleus pulposus (NP) cells. In addition, we investigated Nrf2 expression in NP tissue samples from patients with different degrees of IVD degeneration and a mouse model of aging and IVD degeneration and the influence of H2O2-induced oxidative stress on autophagic pathways in NP cells. Autophagy was assessed by measuring levels of autophagy-related protein (ATG) family members and the autophagic markers, p62 and LC3. We found that expression of Nrf2 progressively decreased in human NP tissue samples of patients with increasing degrees of IVD degeneration. Nrf2 deficiency leads to the degeneration of IVDs during aging. Nrf2 knockout also aggravates IVD degeneration and reduces autophagic gene expression in an induced mouse model of IVD degeneration. The detrimental effects of H2O2-induced oxidative stress were increased in autophagy-deficient cells via reduced expression of Atg7 and the Keap1-Nrf2-p62 autophagy pathway. Taken together, these results suggest that excessive oxidative stress causes the upregulation of autophagy, and autophagy acts as an antioxidant feedback response activated by a Keap1-Nrf2-p62 feedback loop in IVD degeneration.
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页数:12
相关论文
共 34 条
[11]   The autophagy pathway maintained signaling crosstalk with the Keap1-Nrf2 system through p62 in auditory cells under oxidative stress [J].
Hayashi, Ken ;
Dan, Katsuaki ;
Goto, Fumiyuki ;
Tshuchihashi, Nana ;
Nomura, Yasuyuki ;
Fujioka, Masato ;
Kanzaki, Sho ;
Ogawa, Kaoru .
CELLULAR SIGNALLING, 2015, 27 (02) :382-393
[12]   Oxidative stress participates in age-related changes in rat lumbar intervertebral discs [J].
Hou, Gang ;
Lu, Huading ;
Chen, Mingjuan ;
Yao, Hui ;
Zhao, Huiqing .
ARCHIVES OF GERONTOLOGY AND GERIATRICS, 2014, 59 (03) :665-669
[13]   Effects of mechanical compression on metabolism and distribution of oxygen and lactate in intervertebral disc [J].
Huang, Chun-Yuh ;
Gu, Wei Yong .
JOURNAL OF BIOMECHANICS, 2008, 41 (06) :1184-1196
[14]   The effects of microenvironment in mesenchymal stem cell-based regeneration of intervertebral disc [J].
Huang, Yong-Can ;
Leung, Victor Y. L. ;
Lu, William W. ;
Luk, Keith D. K. .
SPINE JOURNAL, 2013, 13 (03) :352-362
[15]   Phosphorylation of p62 Activates the Keap1-Nrf2 Pathway during Selective Autophagy [J].
Ichimura, Yoshinobu ;
Waguri, Satoshi ;
Sou, Yu-shin ;
Kageyama, Shun ;
Hasegawa, Jun ;
Ishimura, Ryosuke ;
Saito, Tetsuya ;
Yang, Yinjie ;
Kouno, Tsuguka ;
Fukutomi, Toshiaki ;
Hoshii, Takayuki ;
Hirao, Atsushi ;
Takagi, Kenji ;
Mizushima, Tsunehiro ;
Motohashi, Hozumi ;
Lee, Myung-Shik ;
Yoshimori, Tamotsu ;
Tanaka, Keiji ;
Yamamoto, Masayuki ;
Komatsu, Masaaki .
MOLECULAR CELL, 2013, 51 (05) :618-631
[16]   Responses and adaptations of intervertebral disc cells to microenvironmental stress: a possible central role of autophagy in the adaptive mechanism [J].
Jiang, Libo ;
Yuan, Fenglai ;
Yin, Xiaofan ;
Dong, Jian .
CONNECTIVE TISSUE RESEARCH, 2014, 55 (5-6) :311-321
[17]   Systems-Level Feedbacks of NRF2 Controlling Autophagy upon Oxidative Stress Response [J].
Kapuy, Orsolya ;
Papp, Diana ;
Vellai, Tibor ;
Banhegyi, Gabor ;
Korcsmaros, Tamas .
ANTIOXIDANTS, 2018, 7 (03)
[18]   Two sesquiterpene aminoquinones protect against oxidative injury in HaCaT keratinocytes via activation of AMPKα/ERK-Nrf2/ARE/HO-1 signaling [J].
Liu, Li ;
Wu, Wei ;
Li, Jing ;
Jiao, Wei-Hua ;
Liu, Li-Yun ;
Tang, Jie ;
Liu, Lei ;
Sun, Fan ;
Han, Bing-Nan ;
Lin, Hou-Wen .
BIOMEDICINE & PHARMACOTHERAPY, 2018, 100 :417-425
[19]   Role of Nrf2 in Oxidative Stress and Toxicity [J].
Ma, Qiang .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 53, 2013, 2013, 53 :401-+
[20]   The Keap 1-Nrf2 system in cancers: stress response and anabolic metabolism [J].
Mitsuishi, Yoichiro ;
Motohashi, Hozumi ;
Yamamoto, Masayuki .
FRONTIERS IN ONCOLOGY, 2012, 2