Abstract Number: OC 06.4
Meeting: ISTH 2020 Congress
Background: Diabetic nephropathy (dNP) is the leading cause of end stage renal disease worldwide. A major therapeutic obstacle in dNP is the failure of renal recovery upon improved blood glucose levels, a phenomenon known as hyperglycemic memory. Epigenetic changes were linked to this memory but the actual mechanisms remain largely elusive. Activated protein C (aPC) has been shown to epigenetically restrict ROS generation in dNP. However, whether aPC could reverse the hyperglycemic memory is currently not known.
Aims: To identify mechanisms contributing to the hyperglycemic memory in dNP and whether aPC can therapeutically reverse the hyperglycemic memory.
Methods: Two mouse models of type 1 and 2 diabetes with established dNP were used. Blood glucose was normalized using an SGLT2-inhibitor. RNA-seq was used to evaluate pathways involved in hyperglycemic memory. In vitro and in vivo studies were conducted to determine mechanistic and translational relevance of aPC role targeting the hyperglycemic memory.
Results: The senescence-associated cyclin dependent kinase inhibitor p21 was among the top persistently induced genes despite blood glucose lowering while protein C gene was downregulated. Sustained tubular expression of p21 was confirmed in diabetic mice and in human patients despite blood glucose lowering. Sustained p21 expression was linked with demethylation of its promoter and reduced DNA methyl transferase 1 (DNMT1) expression. In silico analysis identified miR-148a as a potential regulator of DNMT1. Increased tubular senescence and interstitial fibrosis were confirmed in diabetic mice with genetic deficiency of protein C activation. Substituting aPC or mimicking biased aPC-signaling (parmodulin-2) in addition to normalizing blood glucose levels reversed sustained tubular p21 expression, tubular senescence, and renal damage in mice with established dNP via regulating miR-148a-dependent DNMT1 activity.
Conclusions: Epigenetically sustained p21-expression and associated senescence contribute to the hyperglycemic memory in dNP. This pathogenic mechanism can be targeted by mimicking aPC signaling.
To cite this abstract in AMA style:Elwakiel A, Al-Dabet MM, Shahzad K, Sulaj A, Dockendorff C, Geffers R, Griffin J, Kohli S, Isermann B. Activated Protein C Reverses the p21-Mediated Hyperglycemic Memory in Diabetic Nephropathy [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/activated-protein-c-reverses-the-p21-mediated-hyperglycemic-memory-in-diabetic-nephropathy/. Accessed December 6, 2023.
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