OC 28.3 - Coagulation factor XII induces persistent uPAR-integrin β1 signaling promoting DNA damage and senescence in diabetic kidneys

Sunday, July 10, 2022

3:15 PM – 3:30 PM

Location: ExCel Center, ICC Capital Suite Room 17

Presentation Format: In-Person

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)

Khurrum Shahzad

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

Ihsan Gadi

Scientist
Institute of laboratory medicine, clinical chemistry and molecular diagnostics, Leipzig University
Leipzig, Sachsen, Germany
RR

Rajiv Rana

PhD student
Institute of laboratory medicine, clinical chemistry and molecular diagnostics, Leipzig University
Leipzig, Sachsen, Germany
Dheerendra Gupta, Msc

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

Jayakumar Manoharan

PhD student
Institute of laboratory medicine, clinical chemistry and molecular diagnostics, Leipzig University
Leipzig, Sachsen, Germany
SK

Shrey Kohli, PhD

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

Thomas Renné

Head of Department
Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrum für Diagnostik, UKE, Hamburg, Germany
Hamburg, Hamburg, Germany
Berend Isermann, PhD MD

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

Background: Diabetic kidney disease (DKD) is the leading cause of renal failure worldwide. Diabetes is associated with impaired coagulation system proteins. Whether FXII signaling, which has been linked with a number of inflammatory and fibrotic diseases, plays a role in DKD is currently unknown.

Aims: To identify the role of coagulation FXII in DKD and to elucidate the involved signaling mechanisms.

Methods: Persistent type-1 diabetes was induced and maintained for 24 weeks in wild type (wt) and FXII knockout mice (FXII-/-). Kidney bulk RNA sequencing was performed to identify possible involved pathways. Ex-vivo analyses of human and mice samples and in vitro work were conducted to obtain mechanistic insights.

Results: Increased renal tubular expression of FXII was observed in human and mouse diabetic kidneys. Additionally, FXII was significantly increased in urine samples obtained from two independent DKD human cohorts. Diabetic FXII-/- mice showed reduced albuminuria and renal histopathological changes compared to diabetic wt mice. RNA sequencing revealed differential expressed genes (DEGs) in diabetic FXII-/- versus diabetic wt mice. Functional annotation of DEGs identified pathways related to cell cycle checkpoints associated with DNA damage, senescence, and integrin signaling. Mechanistically, FXII induced and stabilized renal tubular expression of urokinase‐type plasminogen activator receptor (uPAR), which has been linked to senescence and is known to signal through integrins. FXII induced prolonged tubular uPAR signaling via integrin β1. This signaling axis promoted ROS generation, persistent DNA damage, and senescence. Blocking uPAR or integrin β1 ameliorated FXII-induced deleterious effects. Targeting FXII in mice with established DKD using morpholino oligos halted DKD progression and partially reversed the disease.

Conclusion(s): FXII-uPAR-integrin β1 signaling axis promotes renal tubular DNA damage and senescence in diabetic kidneys. Inhibition of FXII or the related signaling pathway could be a promising therapeutic approach to prevent senescence in DKD and to halt the progression of the disease.