Aims
To evaluate whether sodium-glucose cotransporter-2 (SGLT2) inhibition reduces cellular senescence in the kidney and to investigate the molecular pathways involved in the renoprotective effect. Materials and
Conclusions
Dapagliflozin prevented the progression of diabetic kidney disease by inhibiting cellular senescence and oxidative stress via ketone-induced NRF2 activation.
Methods
Dapagliflozin (1 mg/kg), glimepiride (2.5 mg/kg) or vehicle was administered daily via oral gavage for 8 weeks in db/db mice. Expression levels of ageing marker genes (p21, p16, and p53) and oxidative stress were measured in the kidney using real-time RT-PCR, immunohistochemistry, and Western blot analysis. For in vitro analysis, HK-2 cells, a human renal tubular epithelial cell line, were pretreated with H2 O2 to induce cellular senescence, and the levels of ageing markers were measured after treatment with β-hydroxybutyrate (β-HB) or NRF2-specific siRNA.
Results
Expression levels of ageing marker genes (p21, p16 and p53) and senescence-associated secretory phenotypes of the kidney were increased in the vehicle-treated db/db (db/db + vehicle) group compared with the db/+ group, and this increase was markedly reversed in the dapagliflozin-treated db/db (db/db + SGLT2 inhibitor) group, but not in the glimepiride-treated db/db (db/db + sulphonylurea [SU]) group. In the kidneys of mice in the db/db + SGLT2 inhibitor group, oxidative stress and DNA damage were also reduced compared with those of mice in the db/db + vehicle and db/db + SU groups. Dapagliflozin increased plasma β-HB, which reduced H2 O2 -induced DNA damage and senescence in HK-2 cells. β-HB-induced NRF2 nuclear translocation mediated anti-senescent effects by inducing antioxidant pathways. Conclusions: Dapagliflozin prevented the progression of diabetic kidney disease by inhibiting cellular senescence and oxidative stress via ketone-induced NRF2 activation.