Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney: Antifibrotic effects of dapagliflozin

Abstract

Diabetic kidney disease is a worldwide epidemic and therapies are incomplete. Clinical data suggest that improved renal outcomes by SGLT2i are partly beyond their antihyperglycemic effects, however the mechanisms are still elusive. Here we investigated the effect of SGLT2i dapagliflozin (DAPA) in the prevention of elevated OGlcNAcylation and tubular hypoxia as contributors of renal fibrosis. Type 1 diabetes was induced by streptozotocin in adult male Wistar rats. After the onset of diabetes, rats were treated for 6 weeks with a DAPA or DAPA combined with losartan (LOS). The effect of hyperglycemia was tested in HK-2 cells kept under normal or high glucose conditions. To test the effect of hypoxia cells were kept in 1% O2 for 2 hours. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed the loss of renal function, mitigated renal tubular injury markers (KIM-1, NGAL) and reduced tubulointerstitial fibrosis. DAPA diminished high glucose-induced protein OGlcNAcylation and moderated the tubular response to hypoxia through the HIF pathway. DAPA alone was as effective as combined treatment with losartan in all outcome parameters. These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia and fibrosis, a vicious trio that could be targeted by SGLT2i in kidney diseases of other origins as well.