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 <i>Nrf2</i><sup>-/-</sup>/<i>Nrf2<sup>RPTC</sup></i>
transgenic (Tg) mice. Immortalized human RPTCs (HK2) stably transfected with plasmid
containing the <i>SGLT2</i> 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 <i>Nrf2</i><sup>-/-</sup>/<i>Nrf2<sup>RPTC</sup></i> Tg mice compared to their Akita <i>Nrf2</i><sup>-/-</sup> littermates. <i>In vitro</i>, oltipraz or transfection of <i>NRF2</i> cDNA stimulated SGLT2 expression
and <i>SGLT2</i> promoter activity in HK2, and
these effects were inhibited by trigonelline or <i>NRF2 </i>small interfering RNA. The deletion of the <i>NRF2</i>-<i>responsive
element (NRF2-RE)</i> in the <i>SGLT2</i> promoter
abolished the stimulatory effect of oltipraz on <i>SGLT2 </i>promoter activity. NRF2 binding to the <i>NRF2</i>-<i>RE</i>
of the <i>SGLT2</i> 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.
Contribution of a Nuclear Factor-κB Binding Site to Human Angiotensinogen Promoter Activity in Renal Proximal Tubular Cells
