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Abstract: SA-PO353

Complement Activation Mediates Accelerated Tubular and Glomerular Inflammaging in Adriamycin (Adr)-Induced FSGS

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Castellano, Giuseppe, University of Bari, BARI, Italy
  • Stasi, Alessandra, University of Bari, BARI, Italy
  • Divella, Chiara, University of Bari, BARI, Italy
  • Franzin, Rossana, University of Bari, BARI, Italy
  • Sallustio, Fabio, University of Bari, BARI, Italy
  • Curci, Claudia, University of Bari, BARI, Italy
  • Pontrelli, Paola, University of Bari-Dept. of Emergency and Organ Transplantation, Bari, Italy
  • Gesualdo, Loreto, University of Bari, BARI, Italy
  • Cravedi, Paolo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background

Complement activation and chronic low-grade inflammation (inflammaging) have been implicated in renal disease progression. Whether complement activation on podocytes promotes inflammaging and mediates progression of FSGS is unknown.

Methods

We stimulated human primary podocytes with C5a (10-7M) and H2O2 (300μM; positive control) for 24h and then we measured p21 gene expression by qPCR to assess senescence. Then, we injected newly developed DAFfl/fl podocin-CrePOS and DAFfl/fl podocin-CreNEG controls (on a B6 background) with Adr (20mg/kg, i.v.). We serially measured urine albumin/creatinine (A/C) and at 6 weeks we quantified histological injury and stained sections for complement activation products and for senescence markers (WNT4, β-catenin, and p16INK4a).

Results

C5a stimulation induced cellular senescence in podocytes as demonstrated by an increase in p21 marker in vitro (p<0.05).While podocin-CRENEG mice were resistant to Adr, DAFfl/fl-podocin-CrePOS had glomerular deposition of C3b and severe proteinuria (albumin/creatinine: 788.9±342.7 vs. 52.8±59.1mg/g; P<0.05). Immunohistochemistry analyses showed that DAFfl/fl-podocin-CrePOS had a significant increase in tubular WNT4, β-catenin and p16INK4a expression in the nuclei compared to podocin-CRENEG mice (p<0.05). Podocytes and epithelial cells of Bowman’s capsule also showed significantly increased WNT4 and β-catenin expression in DAFfl/fl-podocin-CrePOS compared to podocin-CRENEG animals (p<0.05) (Figure).

Conclusion

We demonstrated that DAF deficiency and complement activation induce accelerated senescence in podocytes and tubular epithelium. These data provide a rationale for testing inhibition of cell senesce as a strategy to retard complement-mediated renal disease progression.