TY - JOUR
T1 - Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis
AU - Angeletti, Andrea
AU - Cantarelli, Chiara
AU - Petrosyan, Astgik
AU - Andrighetto, Sofia
AU - Budge, Kelly
AU - D'Agati, Vivette D
AU - Hartzell, Susan
AU - Malvi, Deborah
AU - Donadei, Chiara
AU - Thurman, Joshua M
AU - Galešić-Ljubanović, Danica
AU - He, John Cijiang
AU - Xiao, Wenzhen
AU - Campbell, Kirk N
AU - Wong, Jenny
AU - Fischman, Clara
AU - Manrique, Joaquin
AU - Zaza, Gianluigi
AU - Fiaccadori, Enrico
AU - La Manna, Gaetano
AU - Fribourg, Miguel
AU - Leventhal, Jeremy
AU - Da Sacco, Stefano
AU - Perin, Laura
AU - Heeger, Peter S
AU - Cravedi, Paolo
N1 - © 2020 Angeletti et al.
PY - 2020/9/7
Y1 - 2020/9/7
N2 - 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.
AB - 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.
KW - Actin Cytoskeleton/metabolism
KW - Aged
KW - Animals
KW - CD55 Antigens/deficiency
KW - Cell Line, Transformed
KW - Complement Activation/immunology
KW - Complement C3b/metabolism
KW - Diabetes Mellitus, Experimental/pathology
KW - Disease Susceptibility
KW - Down-Regulation
KW - Doxorubicin/adverse effects
KW - Female
KW - Glomerulosclerosis, Focal Segmental/chemically induced
KW - Humans
KW - Interleukin-1beta/metabolism
KW - Male
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Middle Aged
KW - Organ Specificity
KW - Phospholipase D/metabolism
KW - Podocytes/metabolism
KW - Receptors, Complement/metabolism
KW - Signal Transduction
U2 - 10.1084/jem.20191699
DO - 10.1084/jem.20191699
M3 - Article
C2 - 32717081
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 9
ER -