BACKGROUND AND OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) is the main 
luminal glucose transporter in the kidney. SGLT2 inhibition results in 
glycosuria and improved glycaemic control. Drugs inhibiting this transporter 
have recently been approved for clinical use and have been suggested to have 
potential renoprotective benefits by limiting glycotoxicity in the proximal 
tubule. We aimed to determine the renoprotective benefits of empagliflozin, an 
SGLT2 inhibitor, independent of its glucose lowering effect.
RESEARCH DESIGN AND METHODS: We induced diabetes using a low dose streptozotocin 
protocol in 7-8 week old endothelial nitric oxide (eNOS) synthase knockout mice. 
We measured fasting blood glucose on a monthly basis, terminal urinary 
albumin/creatinine ratio. Renal histology was assessed for inflammatory and 
fibrotic changes. Renal cortical mRNA transcription of inflammatory and 
profibrotic cytokines, glucose transporters and protein expression of SGLT2 and 
GLUT1 were determined. Outcomes were compared to diabetic animals receiving the 
angiotensin receptor blocker telmisartan (current best practice).
RESULTS: Diabetic mice had high matched blood glucose levels. Empagliflozin did 
not attenuate diabetes-induced albuminuria, unlike telmisartan. Empagliflozin 
did not improve glomerulosclerosis, tubular atrophy, tubulointerstitial 
inflammation or fibrosis, while telmisartan attenuated these. Empagliflozin did 
not modify tubular toll-like receptor-2 expression in diabetic mice. 
Empagliflozin did not reduce the upregulation of macrophage chemoattractant 
protein-1 (MCP-1), transforming growth factor β1 and fibronectin mRNA observed 
in the diabetic animals, while telmisartan decreased transcription of MCP-1 and 
fibronectin. Empagliflozin increased GLUT1 mRNA expression and telmisartan 
increased SGLT2 mRNA expression in comparison to untreated diabetic mice. 
However no significant difference was found in protein expression of GLUT1 or 
SGLT2 among the different groups.
CONCLUSION: Hence SGLT2 inhibition does not have renoprotective benefits 
independent of glucose lowering.