Abstract: FR-PO184
Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Deficiency Attenuates Hyperglycemia, Hypertension, and Nephropathy via Downregulation of Sodium-Glucose Co-Transporter 2 Expression in db/db Mice
Session Information
- Diabetic Kidney Disease: Basic - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Zhao, Shuiling, CRCHUM,University of Montreal, Montreal, Quebec, Canada
- Ghosh, Anindya, CRCHUM, University of Montreal, Montreal, Quebec, Canada
- Miyata, Kana N., CRCHUM,University of Montreal, Montreal, Quebec, Canada
- Lo, Chao-Sheng, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada
- Chenier, Isabelle, CRCHUM,University of Montreal, Montreal, Quebec, Canada
- Filep, Janos G., Maisonneuve-Rosemont Hosp., Montreal, Quebec, Canada
- Ingelfinger, Julie R., The New England Journal of Medicine, Boston, Massachusetts, United States
- Zhang, Shao-Ling, CRCHUM,University of Montreal, Montreal, Quebec, Canada
- Chan, John S.D., CRCHUM,University of Montreal, Montreal, Quebec, Canada
Background
Sodium-glucose co-transporter 2 (Sglt2) expression is up-regulated in renal proximal tubules (RPTs) in the diabetic kidney. The underlying molecular mechanisms, however, remain undefined. We have identified putative nuclear factor erythroid 2-related factor 2 (Nrf2)-responsive elements (REs) in mouse and human Sglt2 gene promoters. We investigated the impact of global Nrf2 knockout (KO) in db/db mice and transgenic (Tg) mice specifically overexpressing Nrf2 in renal proximal tubules (RPTs) on Sglt2 expression and studied the underlying mechanisms of NRF2-regulation of SGLT2 transcription in vitro.
Methods
Male and female db/m, db/m Nrf2 KO, db/db and db/db Nrf2 KO mice were studied up to age 16 weeks. Body weight (BW), blood glucose (BG), systolic blood pressure (SBP) and urinary albumin/creatinine ratio (ACR) were measured at week 16. Nrf2 and Sglt2 expression in isolated RPTs were assessed by RT-qPCR and western blotting. Tg mice specifically overexpressing Nrf2 in their RPTs by employing kidney-specific androgen-regulated promoter were studied. In vitro, the effect of oltipraz (Olz, an Nrf2 activator) and overexpression of NRF2 cDNA on SGLT2 expression and SGLT2 promoter activity in human RPTC (HK-2) were assessed.
Results
BW, BG, SBP, kidney weight/tibia length ratio, ACR, Nrf2 and Sglt2 expression in RPTs were significantly increased in db/db mice as compared to db/m mice. Genetic deletion of Nrf2 significantly attenuated these changes except BW in db/db Nrf2 KO mice. Nrf2 and Sglt2 expression were also significantly increased in RPTs of Nrf2-Tg mice compared to non-Tg mice. In vitro, Olz or overexpression of NRF2 cDNA significantly increased SGLT2 expression and SGLT2 promoter activity via NRF2-REs in the SGLT2 promoter in HK-2.
Conclusion
Nrf2 deficiency attenuates hyperglycemia, hypertension, kidney injury and RPT Sglt2 expression in db/db mice. Overexpression of Nrf2 increases RPT Sglt2 expression in Nrf2-Tg mice. NRF2 stimulates SGLT2 transcription via NRF2-REs in HK-2. These results identify a novel mechanism by which Nrf2 mediates hyperglycemia-stimulation of Sglt2 expression in diabetes.
Funding
- Government Support - Non-U.S.