Regression of diabetic nephropathy by treatment with empagliflozin in BTBR ob/ob mice

Abstract

ABSTRACT Background The SGLT2 inhibitor empagliflozin lowers blood glucose via reduced tubular reabsorption of filtered glucose and is an important new therapy for diabetic nephropathy (DN). This study tested whether treatment with empagliflozin would ameliorate proteinuria and the pathologic alterations of DN including podocyte number and integrity in the leptin deficient BTBR ob/ob mouse model of DN. Methods Study cohorts included wild type BTBR mice, untreated diabetic BTBR ob/ob mice, and mice treated with empagliflozin for six weeks after development of established DN at 18 weeks of age. Results Hyperglycemia, proteinuria, serum creatinine, accumulation of mesangial matrix and the extent of mesangiolysis were reversed with empagliflozin treatment. Treatment with empagliflozin resulted in increased podocyte number and podocyte density, improvement in the degree of podocyte foot process effacement and parietal epithelial cell activation. SGLT2 inhibition reduced renal oxidative stress, measured by urinary excretion of markers of RNA/DNA damage and in situ demonstration of decreased carbonyl oxidation. There was no discernable difference in accumulations of advanced glycation endproducts by immunohistochemistry. Conclusion The structural improvements seen in BTBR ob/ob mice treated with empagliflozin provide insight into potential long term benefits for humans with DN, for whom there is no comparable biopsy information to identify structural changes effected by SGLT2 inhibition. The findings suggest SGLT2 inhibition may ameliorate diabetic nephropathy through glucose lowering-dependent and -independent mechanisms that lead to podocyte restoration and delay or reversal of the disease progress.