Overexpression of Nrf2 in Renal Proximal Tubular Cells Stimulates Sodium-Glucose Co-Transporter 2 Expression and Exacerbates Dysglycemia and Kidney Injury in Diabetic Mice

We 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^-/-/Nrf2^RPTC 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^-/-/Nrf2^RPTC 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.