Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis

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

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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.

Original languageEnglish
Article number20191699
JournalJournal of Experimental Medicine
Issue number9
StatePublished - Jul 2020


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