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, Vol. 15, No. 1, 11.09.2024, p. 7963.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -