Overexpression of Nrf2 Increases Sglt2 Gene Expression and Exacerbates Dysglycemia and Nephropathy Progression in Diabetic Transgenic Mice

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Background: Nuclear factor erythroid-2 related factor 2 (Nrf2), a transcription factor abundantly expressed in renal proximal tubule cells (RPTCs), possesses cytoprotective effects. However, clinical trial with Nrf2 activator (bardoxolone methyl) in T2D patients increased mortality, heart failure rates, heightened hypertension and albuminuria without favorable effect on end-stage kidney disease (ESKD), though the underlying mechanism(s) remain unknown. We reported previously that Nrf2 deficiency ameliorates hyperglycemia and kidney injury in diabetic Akita (T1D) mice, and we identified putative NRF2-binding sites in the promoter of SGLT2. We here hypothesized that overexpression of Nrf2 may upregulate Sglt2 expression and contribute to nephropathy progression in diabetes. Methods: We generated Akita Nrf2-/-/Nrf2RPTC-Tg mice by cross-breeding Akita Nrf2 knockout mice (Akita Nrf2-/-) with Nrf2 transgenic mice (Nrf2RPTC-Tg) overexpressing Nrf2 in RPTCs, studying them until age 20 weeks. Immortalized human RPTC (HK2) stably transfected with plasmid containing SGLT2 gene promoter were also used. Results: Akita Nrf2-/-/Nrf2RPTC Tg mice had increased blood glucose, glomerular filtration rate, urinary albumin-creatinine ratio, tubulointerstitial fibrosis and Sglt2 expression as compared to their Akita Nrf2-/- littermates. In vitro, addition of oltipraz (a Nrf2 activator) or transfection of NRF2 cDNA increased SGLT2 mRNA expression and promoter activity in HK2; these effects were blocked by small interference (si) RNA of NRF2. Deletion of NRF2-responsive elements (NRF2-REs) in the SGLT2 promoter abolished the stimulatory effect of oltipraz on SGLT2 promoter activity. NRF2 bound to NRF2-REs of SGLT2 promoter was seen on gel mobility shift and chromatin immunoprecipitation assays. Conclusions: Our results identify a novel mechanism by which NRF2 mediates hyperglycemia (oxidative stress)-stimulation of SGLT2 expression and exacerbates dysglycemia and kidney injury in diabetes. Funding: Government Support - Non-U.S.

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