Abstract: SA-PO0314
Activated Protein C Epigenetically Regulates DNMT1 Expression and the Sustained Hyperglycemic Memory in Diabetic Kidney Disease by Targeting miR-148a-3p
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 2
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Elwakiel, Ahmed, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, SN, Germany
- Al-Dabet, Moh'd Mohanad Ahmad, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, SN, Germany
- Rana, Rajiv, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, SN, Germany
- Kohli, Shrey, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, SN, Germany
- Isermann, Berend Heinrich, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, SN, Germany
Background
Activated protein C (aPC) reverses the sustained expression of the senescence-associated cell cycle inhibitor p21 and hence the hyperglycemic memory in diabetic kidney disease (DKD) by regulating DNA methyltransferase-1 (DNMT1). How aPC regulates DNMT1 in the context of DKD remains unknown.
Methods
We conducted in silico analyses to identify the top microRNA (miRNA) regulators of DNMT1. The expression of the target miRNAs was studied in kidneys of a murine DKD model and in control and glucose-stimulated kidney tubular cells in vitro. Mechanistic relevance of the identified miRNA for the effects of aPC was studied in vitro and in vivo using specific locked nucleic acid.
Results
miR-148a-3p was identified in silico as a top regulator of DNMT1 expression. Increased expression of miR-148a-3p in the kidneys of wild-type diabetic mice was confirmed. This was associated with DNMT1 suppression. miR-148a-3p expression was reduced in diabetic APChigh mice, that have increased plasma levels of aPC, which has been shown to increase DNMT1 expression. High glucose treatment induced miR-148a-3p expression in kidney tubular cells and the expression remained sustained despite glucose reduction. Exposure to aPC markedly reduced miR-148a-3p expression in vitro. Treatment of diabetic mice with a locked nucleic acid targeting miR-148a-3p markedly reduced albuminuria and increased DNMT1 expression in the kidneys preventing sustained p21 expression and the associated renal senescence and injury.
Conclusion
Our data identify miR-148a-3p as an epigenetic regulator targeted by aPC to restore DNMT1 expression and hence to reverse the sustained p21-associated senescence phenotype and the hyperglycemic memory in DKD. This identifies an epigenetic mechanism targeted by aPC.
Funding
- Government Support – Non-U.S.