2. Academic Validation
  3. SP600125 suppresses Keap1 expression and results in NRF2-mediated prevention of diabetic nephropathy

SP600125 suppresses Keap1 expression and results in NRF2-mediated prevention of diabetic nephropathy

  • J Mol Endocrinol. 2018 Feb;60(2):145-157. doi: 10.1530/JME-17-0260.
Huan Zhang 1,  Xiuxia Liu 2,  Shanshan Zhou 3,  Ye Jia 4,  Ying Li 5,  Yuguo Song 6 7,  Junnan Wang 8,  Hao Wu 9 10
Affiliations

Affiliations

  • 1 Operating TheaterChina-Japan Union Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
  • 2 Department of Clinical LaboratoryThe Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
  • 3 Cardiovascular CenterThe First Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
  • 4 Department of NephrologyThe First Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
  • 5 Department of DermatologyAffiliated Hospital of Beihua University, Jilin, Jilin, People's Republic of China.
  • 6 Research Institute of Clinical ImmunologyAffiliated Hospital of Beihua University, Jilin, Jilin, People's Republic of China.
  • 7 Research Center for Life SciencesBeihua University, Jilin, Jilin, People's Republic of China.
  • 8 Department of CardiologyThe Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China wuhaobaha@jlu.edu.cn jdeywjn@163.com.
  • 9 Department of NephrologyThe Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China wuhaobaha@jlu.edu.cn jdeywjn@163.com.
  • 10 The '973' National Basic Research Program of ChinaChangchun University of Chinese Medicine, Changchun, Jilin, People's Republic of China.
PMID: 29273684 DOI: 10.1530/JME-17-0260
Abstract

c-Jun N-terminal kinase (JNK) contributes to the pathogenesis of diabetic nephropathy (DN). The JNK Inhibitor SP600125 was reported to ameliorate DN. However, the mechanism remained unclear. We previously reported that SP600125 activated nuclear factor erythroid 2-related factor 2 (NRF2), a governor of the cellular antioxidant defense system, in the aortas of the diabetic mice. Given the critical role of NRF2 in preventing DN, the present study aimed to test whether or not NRF2 is required for SP600125's protection against DN. To test the role of NRF2 in SP600125's effect, streptozotocin-induced C57BL/6 wild-type (WT) and Nrf2-knockout (KO) diabetic mice were treated in the presence or absence of SP600125, for 24 weeks. To explore the mechanism by which SP600125 activates NRF2, mouse mesangial cells (MMCs) were treated with high glucose (HG), in the presence or absence of either SP600125 or JNK siRNA. SP600125 significantly attenuated the diabetes-induced renal oxidative stress, inflammation, fibrosis, pathological change and dysfunction in the WT, but not the Nrf2 KO mice. SP600125 inactivated JNK, inhibited kelch-like ECH-associated protein 1 expression, preserved NRF2 protein and facilitated its nuclear translocation in the kidneys of the WT mice, the effects of which were similarly produced by either SP600125 or JNK siRNA in HG-treated MMCs. Further, both SP600125 and JNK siRNA alleviated HG-induced mesangial oxidative stress and expression of inflammatory and fibrotic genes. The present study demonstrates that NRF2 is required for SP600125's protection against DN. SP600125 activates NRF2 possibly via inhibition of JNK-induced Keap1 expression.

Keywords

JNK; KEAP1; NRF2; antioxidant; diabetic nephropathy.

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