Characterization of Renal Protection by SGLT2 Inhibitor in the Adenine Nephropathy Model

Background: SGLT2 inhibition protects renal function in diabetic and non-diabetic kidney disease. Here we tested its effect on adenine nephropathy, a model of rapidly progressing chronic kidney disease. Methods: Adenine (0.15%)-fed mice were treated with SGLT2 inhibitor dapagliflozin (30 mg/kg, once a day) for 6 weeks. Renal function was assessed with the transdermal glomerular filtration rate technique. Proteomics and metabolomics were performed in isolated kidney cortex. Results: Dapagliflozin prevented decline in renal function in adenine-fed mice. Renal proteomics revealed that dapa preserved energy metabolism and prevented inflammation and fibrosis in adenine-fed mice. Despite a 700-fold increase in urinary glucose excretion in dapa-treated mice, plasma glucose was unchanged. We hypothesized that increased glucose production compensated for the urinary losses. Gluconeogenesis occurs in the renal proximal tubules, using glutamine as a substrate. Renal cortex metabolomics and proteomics showed that glycolysis was increased in adenine-fed mice and that SGLT2 inhibition caused a switch to gluconeogenesis in these mice. Conclusion: SGLT2 inhibition is renoprotective in a model of rapidly progressing kidney disease, accompanied by massive glucosuria and a switch from glucose utilization to production by the kidney. This study suggests that renal gluconeogenesis contributes to the maintenance of normoglycemia during SGLT2 inhibition. Funding: Commercial Support - Pfizer Inc