Diabetic nephropathy (DN), one of the more prevalent microvascular complications in patients diagnosed with
diabetes mellitus, is attributed as the main cause of
end-stage renal disease (
ESRD). Lipotoxicity in podocytes caused by
hyperglycemia has been recognised as a significant pathology change, resulting in the deterioration of the glomerular filtration barrier. Research has demonstrated how
dapagliflozin, a kind of SGLT2i, exhibits a multifaceted and powerful protective effect in DN, entirely independent of the
hypoglycemic effect, with the specific mechanism verified. In this present study, we found that
dapagliflozin has the potential to alleviate apoptosis and restore cytoskeleton triggered by high
glucose (HG) in vivo and in vitro. We also discovered that
dapagliflozin could mitigate podocyte
cholesterol accumulation by restoring the expression of ABCA1, which is the key pathway for
cholesterol outflows. This research also mechanistically demonstrates that the protective effect of
dapagliflozin can be mediated by KLF-5, which is the upstream
transcription factor of ABCA1. Taken together, our data suggest that
dapagliflozin offers significant potential in alleviating podocyte injury and
cholesterol accumulation triggered by high
glucose. In terms of the mechanism, we herein reveal that
dapagliflozin could accelerate
cholesterol efflux by restoring the expression of ABCA1, which is directly regulated by KLF-5.