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Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2020
-
Abstract
- While glomerulosclerosis commonly progresses to kidney failure, its mechanisms are unclear. Using murine models and human samples, the authors show that progressive glomerulosclerosis results from loss of decay-accelerating factor (DAF/CD55) on podocytes, which in turn initiates complement C3aR signaling and downstream IL-1β/IL-1R1–mediated podocyte injury and loss.<br />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.<br />Graphical Abstract
- Subjects :
- Male
0301 basic medicine
Interleukin-1beta
Autoimmunity
Podocyte
decay-accelerating factor
podocyte injury
glomerulosclerosis
0302 clinical medicine
Immunology and Allergy
Complement Activation
Decay-accelerating factor
Cell Line, Transformed
Mice, Knockout
CD55 Antigens
biology
Glomerulosclerosis, Focal Segmental
Podocytes
Middle Aged
Receptors, Complement
Cell biology
Complement cascade
Actin Cytoskeleton
Proteinuria
medicine.anatomical_structure
Organ Specificity
030220 oncology & carcinogenesis
Complement C3b
Female
Disease Susceptibility
Decay-accelerating factor (DAF/CD55)
Signal Transduction
Immunology
Down-Regulation
chemical and pharmacologic phenomena
Article
Diabetes Mellitus, Experimental
Nephrin
03 medical and health sciences
Phospholipase D
medicine
Animals
Humans
Autocrine signalling
Aged
Glomerulosclerosis
medicine.disease
Actin cytoskeleton
C3-convertase
Mice, Inbred C57BL
030104 developmental biology
Doxorubicin
biology.protein
Glomerulosclerosi
C3a receptor
Kidney glomerulosclerosis
Kidney glomerulosclerosis, decay-accelerating factor, podocyte injury
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....912426e75294d48dff69e2a74b5924c4