Sodium‐glucose cotransporter‐2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body‐induced NRF2 activation

Abstract

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 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 H2O2 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 H2O2‐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.

A novel hypothesis linking low‐grade ketonaemia to cardio‐renal benefits with sodium‐glucose cotransporter‐2 inhibitors

“…In another recent study, dapagliflozin reduced markers of cellular senescence, oxidative stress and DNA damage in the kidneys of db/db mice, independent of its glucose‐lowering effect. Further, in this study, BHOB treatment of HK‐2 cells (a human renal tubular epithelial cell line) reduced H 2 O 2 (hydrogen peroxide)‐induced DNA damage and senescence by stimulating nuclear factor erythroid 2–related factor 2 (NRF2) nuclear translocation and activating the antioxidant pathway 46 …”

“…Further, in this study, BHOB treatment of HK-2 cells (a human renal tubular epithelial cell line) reduced H 2 O 2 (hydrogen peroxide)-induced DNA damage and senescence by stimulating nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation and activating the antioxidant pathway. 46 The HDAC inhibitors can also induce regression of ventricular hypertrophy, which is a strong and independent predictor of CV events. 47 In one study, empagliflozin 10 mg for 6 months in patients with T2DM, CV disease and ejection fraction of approximately 58% (n = 97), significantly reduced LV mass compared to placebo, without significant changes in LV ejection fraction or end systolic/diastolic volumes.…”

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

“…The renoprotective effects of dapagliflozin in prediabetes by alleviating obesity-induced renal inflammation, fibrosis, ER stress, apoptosis, and lipid accumulation ( 49 ). Dapagliflozin also slowed the progression of diabetic kidney disease by decreasing cellular senescence and oxidative stress via ketone-induced nuclear erythroid-related factor 2 (NRF2) activation ( 50 ). The vasoprotective effect of dapagliflozin may be due to improved transport of bone marrow-derived haematopoietic cells to the site of vascular injury ( 51 ).…”

Renoprotective mechanisms of SGLT2 inhibitor in diabetic kidney disease

“…Moreover, SGLT2i augments ketogenic effects. Furthermore, β-hydroxybutyrate (β-HB) increased in dapagliflozin-treated mice [41]. Dapagliflozin relieved DNA damage and cellular senescence through β-HB-induced activation of nuclear factor erythroid 2-related factor 2 (NRF2) [41].…”

“…Furthermore, β-hydroxybutyrate (β-HB) increased in dapagliflozin-treated mice [41]. Dapagliflozin relieved DNA damage and cellular senescence through β-HB-induced activation of nuclear factor erythroid 2-related factor 2 (NRF2) [41]. Due to increased urinary glucose excretion by SGLT2i, there is substantial energy and glucose loss, which facilitates the whole-body energy utilization conversion from glucose to fatty acid.…”