Dapagliflozin Significantly Suppresses Glomerular Hypertrophy in Rats with Type 2 Diabetes

Background: Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor developed for the treatment of type 2 diabetes mellitus (DM), is a clinically very effective drug that inhibits the progression of chronic kidney disease with or without type 2 DM. However, the underlying mechanisms are unknown. We performed a histological evaluation to explore the renoprotective effects of SGLT2 inhibitors. Methods: Twenty-four male SDT fatty rats, a model of type 2 diabetes, were divided into four groups: sham + placebo group (n=6), sham + dapagliflozin (dapa, 1.5 mg/kg/day) group (n=6), uni-nephrectomy (UNx) + placebo group (n=6), and UNx + dapa group (n=6). UNx or sham surgery was performed at week 6, rats were euthanized at week 12, and kidneys were harvested for histopathological evaluation. The number and size of podocyte nuclei were determined using Wilms tumor 1 (WT1) immunofluorescence staining, and glomerular tufts were estimated using the podocyte cytoplasmic marker glomerular epithelial protein 1 (GLEEP1) immunoperoxidase. Thirty glomeruli per rat were selected and evaluated using an image analyzer. Results: Dapagliflozin significantly reduced glomerular hypertrophy in both the sham surgery and UNx groups (P<0.0001 and P=0.0099, respectively). However, the suppression was smaller in the UNx group. There were no significant differences in the number or density of podocytes. Conclusion: Dapagliflozin significantly suppressed glomerular hypertrophy in a diabetic rat model. It was suggested that the renoprotective effect of dapagliflozin may be mediated through inhibition of glomerular hypertrophy.