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Abstract: TH-PO019

Decay Accelerating Factor (DAF), Local Complement Inhibitor, Protects from Adriamycin (ADR)-Induced FSGS

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Angeletti, Andrea, Icahn School of Medicine at Mount Sinai, New York, United States
  • Donadei, Chiara, Icahn School of Medicine at Mount Sinai, New York, United States
  • D'Agati, Vivette D., Columbia University College of Physicians and Surgeons, New York, New York, United States
  • Wong, Jenny, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Campbell, Kirk N., Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • La Manna, Gaetano, DIMES, Bologna, Italy
  • Fribourg, Miguel L, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Heeger, Peter S., Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background

The impact of DAF, a cell surface expressed complement regulator, in the pathogenesis of proteinuric glomerular disease, including Adr-induced nephropathy is unknown.

Methods

We injected 20mg/kg Adr into B6 WT, and congenic DAF-/-, DAF-/-C3-/-, DAF-/-C3aR-/- mice and DAFfl/fl crossed to Cre-transgenics; the B6 strain is known to be resistant to Adr nephropathy. We serially measured urine albumin/creatinine (A/C) and at 35 weeks we quantified histological injury and stained sections for complement activation products.

Results

: Adr caused proteinuria in B6 DAF-/- but not in WT (Fig 1A), DAF-/-C3-/-, or DAF-/-C3aR-/- mice, mechanistically implicating DAF-dependent restraint on complement activation and ensuing C3a/C3aR signaling in the disease process (Fig 1B). Using newly developed DAF conditional KOs, absent DAF from podocytes (DAFfl/fl-podocin-Cre+) conferred Adr-sensitivity, while DAFfl/fl-CD11c-Cre+ did not develop disease (Fig 1A). DAF-deficiency-induced proteinuria correlated with higher histological scores (Fig 1C) and glomerular staining for C3b, without C1q, C4b, and MAC. Kidneys from Adr-treated DAF-/-, DAFfl/fl-CD11c-Cre+ but not control mice showed Claudin-1+ parietal epithelial cells (PECs) in the glomerulus.

Conclusion

Podocyte-expressed DAF mediates resistance to Adr-induced glomerular injury in B6 mice. In the absence of DAF, Adr-induced kidney injury is propagated by local C3a/C3aR signaling that likely contributes to PEC recruitment and glomerulosclerosis. Studies addressing a role for DAF/complement in human FSGS and related diseases are warranted.