SGLT2 Inhibitors and Diabetic Nephropathy

A recent study has suggested that inhibition of SGLT2 receptors might help prevent renal tubular damage in diabetic nephropathy. The in vitro study showed that the SGLT2 inhibitor tofogliflozin blocked oxidative stress, as well as inflammatory and proapoptotic reactions induced by high glucose levels in cultured human kidney cells.¹

Tofogliflozin is the most selective inhibitor of SGLT2 receptors. The drug received global approval in 2014 in Japan for the treatment of T2DM, and has yet to receive FDA approval in the US.

SGLT mediated glucose uptake could play a role in the progression of diabetic nephropathy through the creation of reactive oxygen species (ROS) and activation of renal AGE-RAGE (advanced glycation end products-receptor for AGE).

SGLT2 transporters-responsible for about 90% of filtered glucose in the proximal renal tubules-- function at an increased rate in diabetes. A past study in experimental diabetic nephropathy showed that SGLT2 inhibition with empagliflozin suppressed oxidative stress and the formation of AGE, resulting in anti-inflammatory and antifibrotic effects.²

The study looked at the effects of two different concentration of tofogliflozin and the antioxidant N-acetylcysteine (NAC) on cultured human proximal tubular cells exposed to high glucose levels.

Results showed:

• Dose-dependent suppression of glucose entry into tubular cells by tofogliflozin

♦ 3 nM tofogliflozin: 33% decreased glucose uptake

♦ 30 nM tofogliflozin: 50% decreased glucose uptake

• Tofogliflozin 3nM and 30 nM significantly suppressed oxidative stress in tubular cells exposed to high glucose levels for 4 and 24 hours  (30 nM) (P<0.01 for both)

• Tofogliflozin decreased apoptotic cell death and the expression of the monocyte chemoattractant protein-1 (MCP-1) gene induced by 4 hours and 8 days of exposure to high glucose

♦ 24 h: 3nM tofogliflozin P<0.05, 30 nM tofo P<0.05

♦ 8 day: 3nM tofogliflozin P<.05, 30 nM tofogliflozin P<0.05  

♦ MCP-1 is involved in monocyte recruitment and adhesion involved in renal inflammation and fibrosis 

• NAC had similar effects as tofogliflozin

“These observations suggest that glucose overload to tubular cells could elicit inflammatory and proapoptotic reactions in this cell type via oxidative stress generation, whose process is partly mediated by SGLT2…” concluded lead author Sho-Ichi Yamagishi, MD, PhD and colleagues at Kurume School of Medicine in Kurume, Japan. “[T]he present findings suggest that blockade of glucose reabsorption in tubular cells by tofogliflozin could exert beneficial effects on tubulointerstitial damage in diabetic nephropathy by directly preventing the glucotoxicity to proximal tubular cells.”

Take-home Points

• SGLT2- mediated glucose reabsorption may be involved in the inflammatory and proapoptic reactions that damage renal cells exposed to high glucose levels. 

• Decreasing glucose reabsorption with the SGLT2 inhibitor tofogliflozin could decrease oxidative damage caused by high glucose levels in proximal tubule cells.

• Tofogliflozin could play a role in preventing progression of diabetic nephropathy.

The study was funded by Sanofi, Paris, France, the maker of tofogliflozin.

References:

1. Ishibashi Y, et al. Tofogliflozin, a highly selective inhibitor of SGLT2 blocks proinflammatory and proapoptotic effects of glucose overload on proximal tubular cells partly by suppressing oxidative stress generation. Horm Metab Res. 2015 Jul 9.

2. Ojima A, et al. Empagliflozin, an Inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis. Horm Metab Res. 2015 Aug;47(9):686-692.