Beneficial effects on kidney during treatment with sodium-glucose cotransporter 2 inhibitors: proposed role of ketone utilization

摘要

Modestly elevated circulating levels of the ketone beta-hydroxybutyrate (beta OHB) during treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors cause different beneficial effects on organs and cells, depending on the succinyl-CoA:3-ketoacid CoA transferase (SCOT) level. In the failing heart, SCOT is highly expressed/up-regulated, and thus, beta OHB may be an energy source, in addition to fat and glucose oxidation. However, SCOT is not highly expressed/down-regulated in the kidney, and thus, beta OHB may cause different beneficial effects, rather than acting as an alternative energy source in patients with chronic kidney disease (CKD). beta OHB is an endogenous and specific inhibitor of class I histone deacetylases (HDACs) and the NLRP3 inflammasome, accumulates in the kidney because of its decreased utilization as an energy source due to the down-regulation of SCOT, and may induce beneficial effects such as inhibiting inflammation, oxidative stress, and fibrosis. In addition to restoring tubulo-glomerular feedback and improving renal proximal tubule oxygenation, SGLT2 inhibitors may play a renoprotective role by way of beta OHB in patients with CKD.