Affiliation:
1. Shandong Provincial Hospital Affiliated to Shandong First Medical University
2. Shandong University
3. Weifang People's Hospital
Abstract
Abstract
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 already 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 find that dapagliflozin has the potential to alleviate apoptosis and restore cytoskeleton triggered by high glucose (HG). We also discover that dapagliflozin could mitigate podocyte cholesterol accumulation by restoring the expression of ABCA, 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. Results of in vivo experiments also show that dapagliflozin has the potential to alleviate apoptosis and cholesterol accumulation induced by diabetes mellitus condition. The expression of ABCA1 and KLF-5 is also restored by dapagliflozin in vivo. 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.
Publisher
Research Square Platform LLC
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