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Poster Networking

Coagulation Factors and Co-Factors

PB1077 - Factor XII-uPAR interaction drives oxidative DNA damage and senescence in kidney tubular cells under hyperglycemic conditions

Tuesday, June 25, 2024
13:45 – 14:45 ICT
Room: Exhibition Hall

    Presenting Author(s)

  • Ahmed Elwakiel

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

    • Co-Author(s)

  • RR

    Rajiv Rana

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

  • JM

    Jayakumar Manoharan, M.Tech

    Doctoral Researcher
    Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Leipzig, Germany
    Leipzig, Sachsen, Germany

  • Saira Ambreen, phd

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

  • Shrey Kohli, PhD

    Junior Group Leader
    Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Leipzig, Germany
    Leipzig, Sachsen, Germany

  • Khurrum Shahzad

    PostDoc
    University of Leipzig
    Leipzig, Sachsen, Germany

  • TR

    Thomas Renné

    Institute director
    University Medical Center Hamburg-Eppendorf
    Hamburg, Hamburg, Germany

  • Berend Isermann, Prof. Dr. med.

    Director
    Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Leipzig, Germany
    virtuell, Sachsen, Germany

Background: Urokinase‐type plasminogen activator receptor (uPAR) is linked to senescence. FXII signals through uPAR in different cells and promotes inflammation and tissue fibrosis. Whether the FXII-uPAR interaction drives tubular senescence in hyperglycemic kidneys remains unknown.

Aims: To identify the role and molecular interaction of FXII-uPAR signaling in diabetic kidney disease (DKD)-associated tubular senescence.

Methods: Tubular FXII expression and urine-FXII were determined in humans and mice without or with hyperglycemia. The FXII-uPAR interaction was studied in the kidneys of a murine model of diabetes and in control and glucose-stimulated kidney tubular cells in vitro. Structural computational modeling was performed to elucidate the interacting residues of FXII and uPAR. Peptides were synthesized to test the therapeutic potential of targeting this interaction in preventing kidney tubular cell injury in DKD.

Results: Increased tubular expression of FXII was observed in human and mouse diabetic kidneys and urinary FXII was increased in humans with DKD. FXII-uPAR interaction was induced in response to high glucose stimulation. Induction of FXII-uPAR interaction was associated with oxidative DNA damage and senescence. Computational structural modeling identified candidate binding residues in the heavy chain of FXII and in uPAR. Targeting the identified residues using synthetic peptides blocked the FXII-uPAR interaction and ameliorated oxidative DNA damage and senescence in kidney tubular cells and thus DKD.

Conclusion(s): FXII-uPAR signaling axis promotes tubular DNA damage and senescence in DKD. Identification of the candidate interacting residues and testing the inhibitory effects of the peptides targeting this interaction may provide promising therapeutic approaches against senescence in diabetic kidneys and possibly in other pathologies associated with FXII-uPAR-induced senescence.