Antiproteinuric effect of dapagliflozin attenuates tubule-interstitial injury development in subclinical acute kidney injury animal model.

INTRODUCTION: Subclinical acute kidney injury (subAKI) is characterized by markers of tubular injury without changes in glomerular function, being associated with acute kidney injury and chronic kidney disease. The use of dapagliflozin (Dapa) has shown protective effects in different models of kidney diseases. However, its effects on the development of subAKI are still under investigation. Previous results suggested that dapagliflozin effect on proximal tubule epithelial cells may involve protein O-GlcNAcylation. Therefore, we aimed to investigate the effects of dapagliflozin on subAKI and its associated mechanisms. METHODS: Male BALB/c mice (6-8-week-old) were separated in four experimental groups: control (CTL), subAKI, subAKI + Dapa, and Dapa. The subAKI mouse model was induced by albumin overload for 7 days. Treated animals received dapagliflozin (1.0 mg/kg/day) by oral gavage. Renal functional and structural parameters were analyzed. In vitro experiments were performed in LLC-PK1 to test specific effects of dapagliflozin on PTECs. RESULTS: Glomerular structure and function were preserved across all experimental groups. However, subAKI animals exhibited increased albuminuria, urinary β2-microglobulin excretion, and elevated KIM-1 expression, all of which were attenuated by dapagliflozin treatment. In addition, dapagliflozin restored albumin-FITC uptake in the renal cortex of subAKI animals. Consistent with these findings, dapagliflozin prevented the reduction in fluorescein isothiocyanate-conjugated albumin (albumin-FITC) uptake induced by high albumin concentration (20 mg/mL) in LLC-PK1 cells. Furthermore, both (Na++K+)ATPase activity and α1-subunit expression were reduced in the subAKI and subAKI + Dapa groups. To investigate the mechanisms underlying the effects of dapagliflozin, we evaluated the expression of OGA, OGT, and total protein O-GlcNAcylation in the renal cortex. Notably, the increases in OGT expression and total protein O-GlcNAcylation observed in subAKI animals were significantly attenuated by dapagliflozin treatment. CONCLUSION: These results suggest that the protective effect of dapagliflozin on tubule-interstitial injury development in subAKI is associated with the restoration of total protein O-GlcNAcylation balance, thereby contributing to its anti-proteinuric effect. These results indicate that dapagliflozin could be a possible alternative to the treatment of subAKI.