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    Oral Communication

    Fibrinolysis and Proteolysis

    Fibrinolysis and Proteolysis

    OC 37.2 - Activated PC enhances the renal tubular regeneration in diabetic kidney disease

    Monday, June 26, 2023
    11:00 – 11:15 ET
    Room: 524
    Session Available As: On-Demand

      Presenting Author(s)

    • Ahmed Elwakiel, M.Sc.

      PhD student
      Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
      Leipzig, Sachsen, Germany

      • Co-Author(s)

    • Dheerendra Gupta, Msc

      PhD student
      Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany.
      Leipzig, Sachsen, Germany

    • KS

      Kunal Singh

      PhD student
      Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
      Leipzig, Sachsen, Germany

    • Sameen Fatima, MPhil

      PhD student
      Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
      Leipzig, Sachsen, Germany

    • SA

      Saira Ambreen

      PhD student
      Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
      Leipzig, Sachsen, Germany

    • AG

      Anubhuti Gupta

      PhD student
      Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
      Leipzig, Sachsen, Germany

    • Shrey Kohli, PhD

      Group leader
      Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
      Leipzig, Sachsen, Germany

    • Khurrum Shahzad

      Group leader
      Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
      Leipzig, Sachsen, Germany

    • Berend Isermann, PhD MD (he/him/his)

      Institute director
      Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University hospital Leipzig, Leipzig, Germany
      Leipzig, Sachsen, Germany

    Background: Acute on chronic renal injury (ACRI) is a major health problem. Tubulointerstitial damage in diabetic kidney disease (DKD) impairs the outcome of acute kidney injury (AKI), possibly reflecting exhaustion of the renal regenerative capacity in DKD. The role of activated PC (aPC), which protects against DKD progression and reverses glucose-induced tubular senescence, for renal regeneration after AKI has not been elucidated hitherto.

    Aims: To delineate the possible role of aPC in controlling renal tubular cell proliferation and repair in DKD after AKI.

    Methods: A model of ACRI was established in mice with persistent hyperglycemia followed by ischemia-reperfusion injury (IRI). Control mice were compared to mice pre-treated with aPC. Lineage tracing and kidney single-cell RNA sequencing (scRNA-seq) were performed to identify the possible mechanisms of aPC. Ex-vivo analyses of mouse tissues and in vitro work were conducted to gain mechanistic insights.

    Results: DKD markedly aggravated histopathological changes and functional impairment following IRI. Pre-treatment with aPC conveyed renal protection. Lineage tracing studies revealed increased proliferation and expansion of tubular cell clones upon aPC pre-treatment. scRNA-seq showed marked changes in different cell populations in DKD mice subjected to IRI mainly in the tubular and immune cell clusters. Functional annotations identified activation of senescence pathways and inflammatory pathways in tubular cell and immune cell clusters, respectively. Pretreatment with aPC protected against these changes. Mechanistically, aPC treatment reduced oxidative DNA damage and induction of senescence in renal tubular cells, which was associated with increased proliferation and ex-vivo clonal expansion of tubular cells in DKD mice following IRI.

    Conclusion(s): aPC improves the outcome of ACRI by enhancing the regenerative capacity of renal tubular cells and reducing the inflammatory response. In DKD, aPC reverses glucose-induced senescence in tubular cells, thus restoring the regenerative capacity. Therefore, aPC-based therapeutics may provide innovative approaches to ACRI in patients with pre-existing DKD.

    Learning Objectives:

    • to recognize the importance of acute on chronic renal injury (ACRI) as a major health problem among diabetic patients
    • to identify the protective role of activated protein C (aPC) as a possible therapeutic option for ACRI
    • to illustrate the mechanisms behind the protective effects of aPC in ACRI by counteracting senescence-associated renal tubular injury