Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway.

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.

GDF-15 alleviates diabetic nephropathy via inhibiting NEDD4L-mediated IKK/NF-κB signalling pathways.

Podocyte inflammatory injury has been indicated to play a pivotal role in the occurrence and development of diabetic nephropathy (DN). However, the pathogenesis of inflammation remains unclear. Recent researches have shown that GDF-15, a member of the transforming growth factor-ß superfamily, were elevated under pathological conditions, such as myocardial ischemia, cancer, as well as inflammation. Here, we demonstrated that GDF-15 could alleviate podocyte inflammatory injury by modulating the NF-κB pathway. GDF-15 and other pro-inflammatory factors, such as TNF-α, IL-1ß, and IL-6 were upregulated in the serum of HFD/STZ rat models. GDF-15 was also elevated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes. The silence of GDF-15 in HG-stimulated podocytes further augmented inflammation and podocyte injury, while overexpression of GDF-15 significantly reduced the inflammatory response in podocytes. Mechanistically, we demonstrated that GDF-15 could inhibit the nuclear translocation of NF-κB through IKK and IκBα by interaction with ubiquitin ligase NEDD4L. Taken together, our data suggested a protective mechanism of elevated GDF-15 in DN through obstruction of ubiquitin degradation of IKK by inhibiting NEDD4L expression, thus decreasing the activation of NF-κB and relieving the inflammation. GDF-15 could serve as a potential therapeutic target for DN.