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Kidney Week

Abstract: TH-PO893

The p21-Mediated and Senescence-Associated Hyperglycemic Memory in Diabetic Nephropathy Is Therapeutically Amendable

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Kohli, Shrey, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
  • Al-Dabet, Moh'd Mohanad Ahmad, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
  • Elwakiel, Ahmed, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
  • Gadi, Ihsan Khan, Otto-von-Guericke-University, Magdeburg, Germany
  • Sulaj, Alba, University Hospital Heidelberg, Heidelberg, Germany
  • Dockendorff, Chris, Marquette University, Milwaukee, Wisconsin, United States
  • Mertens, Peter R., Otto-von-Guericke-University, Magdeburg, Germany
  • Isermann, Berend Heinrich, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

Diabetic nephropathy (DN) is a major cause of end-stage renal disease. A major challenge in DN is the failure of renal recovery upon improved blood glucose levels. The mechanisms underlying this phenomenon, known as the metabolic memory, remain unknown. We aimed to identify mechanisms contributing to the metabolic memory in DN.


Two mouse models with established DN (16 weeks after STZ-induced persistent hyperglycemia or 16 weeks old db/db mice) were used. Blood glucose was normalized for 6 weeks using an SGLT2-inhibitor. An unbiased approach (mRNA-seq) was used to evaluate pathways involved in metabolic memory. Candidate genes were studied in human diabetic patients and mice after lowering blood glucose. In vitro and in vivo studies were conducted to determine mechanistic and translational relevance.


Despite a marked reduction of blood glucose levels, albuminuria and glucose induced changes in renal gene expression persisted, enabling to study mechanisms contributing to metabolic memory. PI3-kinase-Akt signaling, cellular proliferation and senescence, and complement-coagulation cascades were linked with metabolic memory. Sustained tubular expression of p21 – a senescence-associated cyclin-dependent kinase inhibitor –was confirmed in humans (histology, urinary p21) and mice (histology, RNA, protein) despite blood glucose lowering. Sustained p21 expression was linked with promoter demethylation and reduced DNMT activity and DNMT1 expression. In silico and in vitro analyses identified miR-148a as a potential regulator of DNMT1. The nephroprotective zymogen protein C was among the genes persistently repressed in DN. Increased tubular senescence, interstitial fibrosis, and albuminuria was confirmed in diabetic mice with a superimposed genetic deficiency of protein C activation. Substituting the protease activated protein C (aPC), mimicking biased aPC-signaling (parmodulin-2), or reducing miR-148a in addition to normalizing blood glucose reversed sustained tubular p21 expression, senescence, and renal damage in DN.


Epigenetically sustained p21-expression and associated senescence contribute to the metabolic memory in DN. This pathogenic mechanism can be targeted by inhibiting miR-148a or by mimicking cytoprotective aPC-signaling.


  • Government Support - Non-U.S.