Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway
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 been recognised as a significant pathology...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Diabetology & Metabolic Syndrome |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13098-024-01271-6 |
| _version_ | 1797273718076997632 |
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| author | Jingshu Sun Xinyu Zhang Simeng Wang Dandan Chen Jianqiang Shu Nannan Chong Qinglian Wang Ying Xu |
| author_facet | Jingshu Sun Xinyu Zhang Simeng Wang Dandan Chen Jianqiang Shu Nannan Chong Qinglian Wang Ying Xu |
| author_sort | Jingshu Sun |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-03-07T14:48:17Z |
| format | Article |
| id | doaj.art-0d90c73a04714e699fb22707e5404dd8 |
| institution | Directory Open Access Journal |
| issn | 1758-5996 |
| language | English |
| last_indexed | 2024-03-07T14:48:17Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Diabetology & Metabolic Syndrome |
| spelling | doaj.art-0d90c73a04714e699fb22707e5404dd82024-03-05T19:49:30ZengBMCDiabetology & Metabolic Syndrome1758-59962024-02-0116111210.1186/s13098-024-01271-6Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathwayJingshu Sun0Xinyu Zhang1Simeng Wang2Dandan Chen3Jianqiang Shu4Nannan Chong5Qinglian Wang6Ying Xu7Shandong Provincial Hospital, Shandong UniversityShandong Provincial Hospital, Shandong UniversityShandong Provincial Hospital, Shandong UniversityShandong Provincial Hospital, Shandong UniversityShandong Provincial Hospital, Shandong UniversityDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityShandong Provincial Hospital, Shandong UniversityShandong Provincial Hospital, Shandong UniversityAbstract 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.https://doi.org/10.1186/s13098-024-01271-6DapagliflozinDiabetic NephropathyCholesterolKLF-5ABCA1 |
| spellingShingle | Jingshu Sun Xinyu Zhang Simeng Wang Dandan Chen Jianqiang Shu Nannan Chong Qinglian Wang Ying Xu Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway Diabetology & Metabolic Syndrome Dapagliflozin Diabetic Nephropathy Cholesterol KLF-5 ABCA1 |
| title | Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway |
| title_full | Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway |
| title_fullStr | Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway |
| title_full_unstemmed | Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway |
| title_short | Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway |
| title_sort | dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through klf5 targeting the abca1 signalling pathway |
| topic | Dapagliflozin Diabetic Nephropathy Cholesterol KLF-5 ABCA1 |
| url | https://doi.org/10.1186/s13098-024-01271-6 |
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