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Factor XII signaling via uPAR-integrin ß1 axis promotes tubular senescence in diabetic kidney disease.
Elwakiel, Ahmed; Gupta, Dheerendra; Rana, Rajiv; Manoharan, Jayakumar; Al-Dabet, Moh'd Mohanad; Ambreen, Saira; Fatima, Sameen; Zimmermann, Silke; Mathew, Akash; Li, Zhiyang; Singh, Kunal; Gupta, Anubhuti; Pal, Surinder; Sulaj, Alba; Kopf, Stefan; Schwab, Constantin; Baber, Ronny; Geffers, Robert; Götze, Tom; Alo, Bekas; Lamers, Christina; Kluge, Paul; Kuenze, Georg; Kohli, Shrey; Renné, Thomas; Shahzad, Khurrum; Isermann, Berend.
Afiliação
  • Elwakiel A; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany. ahmed.elwakiel@medizin.uni-leipzig.de.
  • Gupta D; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Rana R; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Manoharan J; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Al-Dabet MM; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Ambreen S; Department of Medical Laboratory Sciences, School of Science, University of Jordan, Amman, Jordan.
  • Fatima S; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Zimmermann S; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Mathew A; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Li Z; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Singh K; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Gupta A; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Pal S; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Sulaj A; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Kopf S; Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany.
  • Schwab C; Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany.
  • Baber R; Institute of pathology, University of Heidelberg, Heidelberg, Germany.
  • Geffers R; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
  • Götze T; Leipzig Medical Biobank, Leipzig University, Leipzig, Germany.
  • Alo B; Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • Lamers C; Institute for Drug Discovery, Faculty of Medicine, Leipzig University, Leipzig, Germany.
  • Kluge P; Institute for Drug Discovery, Faculty of Medicine, Leipzig University, Leipzig, Germany.
  • Kuenze G; Institute for Drug Discovery, Faculty of Medicine, Leipzig University, Leipzig, Germany.
  • Kohli S; Institute for Drug Discovery, Faculty of Medicine, Leipzig University, Leipzig, Germany.
  • Renné T; Institute for Drug Discovery, Faculty of Medicine, Leipzig University, Leipzig, Germany.
  • Shahzad K; Center for Scalable Data Analytics and Artificial Intelligence, Leipzig University, Leipzig, Germany.
  • Isermann B; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
Nat Commun ; 15(1): 7963, 2024 Sep 11.
Article em En | MEDLINE | ID: mdl-39261453
ABSTRACT
Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12-/-) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin ß1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin ß1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin ß1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fator XII / Senescência Celular / Integrina beta1 / Nefropatias Diabéticas / Receptores de Ativador de Plasminogênio Tipo Uroquinase Limite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Reino Unido
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fator XII / Senescência Celular / Integrina beta1 / Nefropatias Diabéticas / Receptores de Ativador de Plasminogênio Tipo Uroquinase Limite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Reino Unido