Diabetic kidney disease is a worldwide epidemic, and therapies are incomplete. Clinical
data suggest that improved renal outcomes by Na -glucose cotransporter 2 inhibitor
(SGLT2i) are partly beyond their antihyperglycemic effects; however, the mechanisms
are still elusive. Here, we investigated the effect of the SGLT2i dapagliflozin (DAPA)
in the prevention of elevated O-GlcNAcylation 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 wk with 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% 02 for 2 h. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed
the loss of renal function, mitigated renal tubular injury markers (kidney injury
molecule-1 and neutrophil gelatinase-associated lipocalin), and reduced tubulointerstitial
fibrosis. DAPA diminished high glucose -induced protein 0-G1cNIAcylation and moderated
the tubular response to hypoxia through the hypoxia-inducible factor pathway. DAPA
alone was as effective as combined treatment with LOS 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 he targeted by
SGLT2i in kidney diseases of other origins as well.
