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Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis (CROSBI ID 310328)

Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija

Angeletti, Andrea ; Cantarelli, Chiara ; Petrosyan, Astgik ; Andrighetto, Sofia ; Budge, Kelly ; D’Agati, Vivette D. ; Hartzell, Susan ; Malvi, Deborah ; Donadei, Chiara ; Thurman, Joshua M. et al. Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis // The Journal of experimental medicine, 217 (2020), 9; e20191699, 24. doi: 10.1084/jem.20191699

Podaci o odgovornosti

Angeletti, Andrea ; Cantarelli, Chiara ; Petrosyan, Astgik ; Andrighetto, Sofia ; Budge, Kelly ; D’Agati, Vivette D. ; Hartzell, Susan ; Malvi, Deborah ; Donadei, Chiara ; Thurman, Joshua M. ; Galešić Ljubanović, Danica ; He, John Cijiang ; Xiao, Wenzhen ; Campbell, Kirk N. ; Wong, Jenny ; Fischman, Clara ; Manrique, Joaquin ; Zaza, Gianluigi ; Fiaccadori, Enrico ; La Manna, Gaetano ; Fribourg, Miguel ; Leventhal, Jeremy ; Da Sacco, Stefano ; Perin, Laura ; Heeger, Peter S. ; Cravedi, Paolo

engleski

Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis

Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay- accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL- 1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement- dependent, IL-1β-induced podocyte injury, potentially identifying new therapeutic targets.

decay-accelerating factor, podocyte injury, glomerulosclerosis

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Podaci o izdanju

217 (9)

2020.

e20191699

24

objavljeno

0022-1007

1540-9538

10.1084/jem.20191699

Povezanost rada

Kliničke medicinske znanosti

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