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SP600125 suppresses Keap1 expression and results in NRF2-mediated prevention of diabetic nephropathy
- Source :
- Journal of Molecular Endocrinology. 60:145-157
- Publication Year :
- 2018
- Publisher :
- Bioscientifica, 2018.
-
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) andNrf2-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 theNrf2KO 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-inducedKeap1expression.
- Subjects :
- 0301 basic medicine
endocrine system
Antioxidant
Kinase
Chemistry
medicine.medical_treatment
Inflammation
respiratory system
Pharmacology
medicine.disease
medicine.disease_cause
environment and public health
KEAP1
Diabetic nephropathy
Pathogenesis
03 medical and health sciences
030104 developmental biology
Endocrinology
Fibrosis
polycyclic compounds
medicine
medicine.symptom
Molecular Biology
Oxidative stress
Subjects
Details
- ISSN :
- 14796813 and 09525041
- Volume :
- 60
- Database :
- OpenAIRE
- Journal :
- Journal of Molecular Endocrinology
- Accession number :
- edsair.doi...........92900cfc99712cc19d629109afee7675