Kidney Week

Abstract: TH-PO019

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

Session Information

• Complement Your Knowledge of Kidney Disease
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

• 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

• Angeletti, Andrea, Icahn School of Medicine at Mount Sinai, New York, United States

Andrea Angeletti,

• Donadei, Chiara, Icahn School of Medicine at Mount Sinai, New York, United States

Chiara Donadei,

• D'Agati, Vivette D., Columbia University College of Physicians and Surgeons, New York, New York, United States

Vivette D. D'Agati,

• Wong, Jenny, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Jenny Wong,

• Campbell, Kirk N., Icahn School of Medicine at Mount Sinai, New York, New York, United States

Kirk N. Campbell,

• La Manna, Gaetano, DIMES, Bologna, Italy

Gaetano La Manna,

• Fribourg, Miguel L, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Miguel L Fribourg,

• Heeger, Peter S., Icahn School of Medicine at Mount Sinai, New York, New York, United States

Peter S. Heeger,

• Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Paolo Cravedi,

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 DAF^fl/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 (DAF^fl/fl-podocin-Cre⁺) conferred Adr-sensitivity, while DAF^fl/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^-/-, DAF^fl/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.