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DNMT1-Mediated the Downregulation of FOXF1 Promotes High Glucose-induced Podocyte Damage by Regulating the miR-342-3p/E2F1 Axis.
- Source :
-
Cell biochemistry and biophysics [Cell Biochem Biophys] 2024 Sep; Vol. 82 (3), pp. 2957-2975. Date of Electronic Publication: 2024 Jul 16. - Publication Year :
- 2024
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Abstract
- Podocyte damage plays a crucial role in the occurrence and development of diabetic nephropathy (DN). Accumulating evidence suggests that dysregulation of transcription factors plays a crucial role in podocyte damage in DN. However, the biological functions and underlying mechanisms of most transcription factors in hyperglycemia-induced podocytes damage remain largely unknown. Through integrated analysis of data mining, bioinformatics, and RT-qPCR validation, we identified a critical transcription factor forkhead box F1 (FOXF1) implicated in DN progression. Moreover, we discovered that FOXF1 was extensively down-regulated in renal tissue and serum from DN patients as well as in high glucose (HG)-induced podocyte damage. Meanwhile, our findings showed that FOXF1 might be a viable diagnostic marker for DN patients. Functional experiments demonstrated that overexpression of FOXF1 strikingly enhanced proliferation, outstandingly suppressed apoptosis, and dramatically reduced inflammation and fibrosis in HG-induced podocytes damage. Mechanistically, we found that the downregulation of FOXF1 in HG-induced podocyte damage was caused by DNMT1 directly binding to FOXF1 promoter and mediating DNA hypermethylation to block FOXF1 transcriptional activity. Furthermore, we found that FOXF1 inhibited the transcriptional expression of miR-342-3p by binding to the promoter of miR-342, resulting in reduced sponge adsorption of miR-342-3p to E2F1, promoting the expression of E2F1, and thereby inhibiting HG-induced podocytes damage. In conclusion, our findings showed that blocking the FOXF1/miR-342-3p/E2F1 axis greatly alleviated HG-induced podocyte damage, which provided a fresh perspective on the pathogenesis and therapeutic strategies for DN patients.<br /> (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Subjects :
- Humans
Animals
Apoptosis drug effects
DNA Methylation
Promoter Regions, Genetic
Mice
Cell Proliferation
Podocytes metabolism
Podocytes pathology
MicroRNAs genetics
MicroRNAs metabolism
Forkhead Transcription Factors metabolism
Forkhead Transcription Factors genetics
Down-Regulation
E2F1 Transcription Factor metabolism
E2F1 Transcription Factor genetics
Diabetic Nephropathies metabolism
Diabetic Nephropathies pathology
Diabetic Nephropathies genetics
Glucose pharmacology
Glucose metabolism
DNA (Cytosine-5-)-Methyltransferase 1 metabolism
DNA (Cytosine-5-)-Methyltransferase 1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1559-0283
- Volume :
- 82
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell biochemistry and biophysics
- Publication Type :
- Academic Journal
- Accession number :
- 39014186
- Full Text :
- https://doi.org/10.1007/s12013-024-01409-3