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Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis

Andrea Angeletti1,2, Chiara Cantarelli1,3, Astgik Petrosyan4,5

  • 1Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

The Journal of Experimental Medicine
|July 28, 2020
PubMed

Insights

Loss of podocyte decay-accelerating factor (DAF/CD55) triggers complement activation and IL-1β signaling, driving glomerulosclerosis progression. Restoring DAF or blocking C3aR/IL-1R1 signaling prevents kidney disease.

Area of Science:

  • Nephrology
  • Immunology
  • Molecular Biology

Background:

  • Glomerulosclerosis often leads to end-stage kidney failure, with unclear pathogenic mechanisms.
  • Podocyte injury is a key factor in glomerulosclerosis development and progression.

Purpose of the Study:

  • To investigate the role of decay-accelerating factor (DAF/CD55) in glomerulosclerosis pathogenesis.
  • To elucidate the molecular mechanisms linking DAF deficiency to complement activation and podocyte injury.

Main Methods:

  • Murine models of adriamycin (ADR)-induced and streptozotocin (STZ)-induced glomerulosclerosis.
  • Analysis of DAF expression, complement activation (C3, C3aR), and IL-1β/IL-1R1 signaling in podocytes.
  • Assessment of nephrin expression and podocyte cytoskeleton integrity.
  • Examination of human FSGS patient glomeruli and urinary C3a levels.

Main Results:

  • Podocyte DAF expression is crucial in preventing glomerulosclerosis in ADR and STZ models.
  • ADR treatment cleaves DAF, leading to complement activation and C3a/C3aR signaling on podocytes.
  • C3 deficiency or C3aR blockade abrogates glomerulosclerosis, confirming complement dependence.
  • C3a/C3aR ligation initiates an IL-1β/IL-1R1 autocrine loop, reducing nephrin and disrupting podocyte cytoskeleton.
  • Blocking IL-1β/IL-1R1 signaling prevents disease development.
  • Human FSGS glomeruli show DAF loss and C3d deposition; urinary C3a correlates with proteinuria.

Conclusions:

  • Loss of podocyte DAF initiates a cascade involving complement activation and IL-1β signaling, causing podocyte injury and glomerulosclerosis.
  • This pathway represents a potential therapeutic target for glomerulosclerosis and related kidney diseases.

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