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Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease

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Factor XII signaling via uPAR-integrin β1 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.

in: NAT COMMUN, Jahrgang 15, Nr. 1, 11.09.2024, S. 7963.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Elwakiel, A, Gupta, D, Rana, R, Manoharan, J, Al-Dabet, MM, Ambreen, S, Fatima, S, Zimmermann, S, Mathew, A, Li, Z, Singh, K, Gupta, A, Pal, S, Sulaj, A, Kopf, S, Schwab, C, Baber, R, Geffers, R, Götze, T, Alo, B, Lamers, C, Kluge, P, Kuenze, G, Kohli, S, Renné, T, Shahzad, K & Isermann, B 2024, 'Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease', NAT COMMUN, Jg. 15, Nr. 1, S. 7963. https://doi.org/10.1038/s41467-024-52214-8

APA

Elwakiel, A., Gupta, D., Rana, R., Manoharan, J., Al-Dabet, M. M., Ambreen, S., Fatima, S., Zimmermann, S., Mathew, A., Li, Z., Singh, K., Gupta, A., Pal, S., Sulaj, A., Kopf, S., Schwab, C., Baber, R., Geffers, R., Götze, T., ... Isermann, B. (2024). Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease. NAT COMMUN, 15(1), 7963. https://doi.org/10.1038/s41467-024-52214-8

Vancouver

Elwakiel A, Gupta D, Rana R, Manoharan J, Al-Dabet MM, Ambreen S et al. Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease. NAT COMMUN. 2024 Sep 11;15(1):7963. https://doi.org/10.1038/s41467-024-52214-8

Bibtex

@article{ec9182da34974304b25046ecb64d4f3d,
title = "Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease",
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 β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 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. ",
keywords = "Animals, Female, Humans, Male, Mice, Cellular Senescence, Diabetic Nephropathies/metabolism, Factor XII/metabolism, Integrin beta1/metabolism, Kidney Tubules/metabolism, Mice, Inbred C57BL, Mice, Knockout, Oxidative Stress, Receptors, Urokinase Plasminogen Activator/metabolism, Signal Transduction",
author = "Ahmed Elwakiel and Dheerendra Gupta and Rajiv Rana and Jayakumar Manoharan and Al-Dabet, {Moh'd Mohanad} and Saira Ambreen and Sameen Fatima and Silke Zimmermann and Akash Mathew and Zhiyang Li and Kunal Singh and Anubhuti Gupta and Surinder Pal and Alba Sulaj and Stefan Kopf and Constantin Schwab and Ronny Baber and Robert Geffers and Tom G{\"o}tze and Bekas Alo and Christina Lamers and Paul Kluge and Georg Kuenze and Shrey Kohli and Thomas Renn{\'e} and Khurrum Shahzad and Berend Isermann",
note = "{\textcopyright} 2024. The Author(s).",
year = "2024",
month = sep,
day = "11",
doi = "10.1038/s41467-024-52214-8",
language = "English",
volume = "15",
pages = "7963",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

TY - JOUR

T1 - Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease

AU - Elwakiel, Ahmed

AU - Gupta, Dheerendra

AU - Rana, Rajiv

AU - Manoharan, Jayakumar

AU - Al-Dabet, Moh'd Mohanad

AU - Ambreen, Saira

AU - Fatima, Sameen

AU - Zimmermann, Silke

AU - Mathew, Akash

AU - Li, Zhiyang

AU - Singh, Kunal

AU - Gupta, Anubhuti

AU - Pal, Surinder

AU - Sulaj, Alba

AU - Kopf, Stefan

AU - Schwab, Constantin

AU - Baber, Ronny

AU - Geffers, Robert

AU - Götze, Tom

AU - Alo, Bekas

AU - Lamers, Christina

AU - Kluge, Paul

AU - Kuenze, Georg

AU - Kohli, Shrey

AU - Renné, Thomas

AU - Shahzad, Khurrum

AU - Isermann, Berend

N1 - © 2024. The Author(s).

PY - 2024/9/11

Y1 - 2024/9/11

N2 - 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 β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 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.

AB - 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 β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 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.

KW - Animals

KW - Female

KW - Humans

KW - Male

KW - Mice

KW - Cellular Senescence

KW - Diabetic Nephropathies/metabolism

KW - Factor XII/metabolism

KW - Integrin beta1/metabolism

KW - Kidney Tubules/metabolism

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Oxidative Stress

KW - Receptors, Urokinase Plasminogen Activator/metabolism

KW - Signal Transduction

U2 - 10.1038/s41467-024-52214-8

DO - 10.1038/s41467-024-52214-8

M3 - SCORING: Journal article

C2 - 39261453

VL - 15

SP - 7963

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

ER -