Decay-Accelerating Factor Restrains Complement Activation and Delays Progression of Murine cBSA-Induced Membranous Nephropathy

Kelly L. Budge, Alberto Verlato, Sofia Bin, Fadi E. Salem, Laura Perin, Gaetano La Manna, Gianluigi Zaza, Enrico Fiaccadori, Chiara Cantarelli, Paolo Cravedi

Research output: Contribution to journalArticlepeer-review

Abstract

BackgroundComplement activation is believed to play a major pathogenic role in membranous nephropathy (MN), but its effector mechanisms are still unclear. Even less investigated is the role of podocyte-expressed complement regulators, including decay-accelerating factor (DAF) in disease pathophysiology.MethodsWe induced MN by serial injections of cationic bovine serum albumin (cBSA) in WT, DAF-/-, and C3aR-/-BALB/c mice and measured disease severity (by albuminuria, BUN, serum albumin, and glomerular histologic changes) and signs of complement activation in the glomeruli (immunofluorescence for C1q, C3b, and membrane attack complex). We also treated DAF-/-mice with cBSA-induced MN with a selective C3aR antagonist and measured the same readouts.ResultscBSA-induced MN was associated with increased glomerular expression of DAF. Genetic deletion of DAF resulted in increased complement activation and higher disease severity than in WT animals. Treating cBSA-injected DAF-/-mice with a C3aR antagonist reduced disease severity. Similarly, C3aR-/-animals were protected from cBSA-induced MN, despite IgG deposition in the glomeruli and complement activation. Evidence of C1q and C3b deposition in the glomeruli of these mice suggest that IgG-cBSA immune complex formation in the glomeruli activates complement through the classical pathway.ConclusionsOn cBSA-induced injury, podocytes upregulate DAF expression, which restrains complement activation. However, after prolonged injury, complement activation overcomes DAF regulatory effects leading to the formation of soluble anaphylatoxin C3a that, by signaling through C3aR, promotes glomerular injury and cBSA-induced MN disease progression. Considering the growing number of complement targeting therapies, our findings may have major translational effect on the treatment of patients with MN.

Original languageEnglish
Pages (from-to)769-776
Number of pages8
JournalKidney360
Volume4
Issue number6
DOIs
StatePublished - 1 Jun 2023

Keywords

  • C3a
  • C3aR
  • DAF
  • classical pathway
  • complement
  • membranous nephropathy

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