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Download fileOverexpression of Nrf2 in Renal Proximal Tubular Cells Stimulates Sodium-Glucose Co-Transporter 2 Expression and Exacerbates Dysglycemia and Kidney Injury in Diabetic Mice
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posted on 2021-04-05, 15:13 authored by Shuiling Zhao, Chao-Sheng Lo, Kana N. Miyata, Anindya Ghosh, Xinping Zhao, Isabelle Chenier, Jean-Francois Cailhier, Jean Ethier, Jean-Baptiste Lattouf, Janos G. Filep, Julie R. Ingelfinger, Shao-Ling Zhang, John S.D. ChanWe
investigated the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) overexpression
in renal proximal tubular cells (RPTCs) on blood glucose, kidney injury and
sodium-glucose co-transporter 2 (Sglt2) expression in diabetic Akita Nrf2-/-/Nrf2RPTC
transgenic (Tg) mice. Immortalized human RPTCs (HK2) stably transfected with plasmid
containing the SGLT2 promoter, human kidneys
from patients with diabetes were also studied. Nrf2 overexpression was
associated with increased blood
glucose, glomerular filtration rate, urinary albumin-creatinine ratio, tubulointerstitial
fibrosis and Sglt2 expression in Akita Nrf2-/-/Nrf2RPTC Tg mice compared to their Akita Nrf2-/- littermates. In vitro, oltipraz or transfection of NRF2 cDNA stimulated SGLT2 expression
and SGLT2 promoter activity in HK2, and
these effects were inhibited by trigonelline or NRF2 small interfering RNA. The deletion of the NRF2-responsive
element (NRF2-RE) in the SGLT2 promoter
abolished the stimulatory effect of oltipraz on SGLT2 promoter activity. NRF2 binding to the NRF2-RE
of the SGLT2 promoter was confirmed by
gel mobility shift assay and chromatin immunoprecipitation assays. Kidneys from patients with diabetes exhibited
higher levels of NRF2 and SGLT2 in the RPTCs than kidneys from patients without
diabetes. These results suggest a link by which NRF2 mediates hyperglycemia-stimulation
of SGLT2 expression and exacerbates blood glucose and kidney injury in
diabetes.