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Kidney Week

Abstract: TH-PO919

Inhibition of Fibronectin Fibrillogenesis Attenuates Progression of Fibrosis in Animal and Kidney Organoid Models

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Xin, Cuiyan, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Gupta, Navin R., Brigham & Women's Hospital/Massachusetts General Hospital, Brighton, Massachusetts, United States
  • Ajay, Amrendra Kumar, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Akinfolarin, Akinwande A., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Garcia, Edgar, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Morizane, Ryuji, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Sabbisetti, Venkata, Brigham and Women's Hospital, Boston, Massachusetts, United States
Background

Renal fibrosis is the principal pathological process underlying the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). Fibronectin (FN) assembly is required for collagen matrix deposition and localized activation of TGF-ß. We hypothesize that interfering with FN polymerization would attenuate fibrosis in in vitro and in vivo kidney fibrosis models.

Methods

Mice were subjected to unilateral ureteral obstruction (UUO) and treated with fibronectin polymerization blocking peptide (pUR4) and control peptide (CIII-11C) to evaluate the therapeutic benefit of blocking FN assembly in attenuating or reversing fibrosis progression. We evaluated the efficacy of pUR4 peptide in attenuating kidney fibrosis in two different treatment modalities. In parallel treatment model, we evaluated the therapeutic efficacy in halting or slowing the progression of fibrosis by injecting pUR4 (i.p, 100 mg/kg) & CIII-11C (i.p, 100 mg/kg) from day 5 - day 10 post-UUO every day. In successive treatment model, we evaluated the efficacy of the pUR4 in halting or reversing the established fibrosis by giving pUR4 from day 10 – day 15 post-UUO. Mice were sacrificed at the end of the study and urine, blood and tissues were collected. Efficacy of pUR4 peptide was also evaluated in cisplatin induced kidney organoid models of fibrosis.

Results

In vivo, pUR4-treatment reduced fibrosis in both parallel and successive model of UUO induced fibrosis. pUR4 treated mice display reduced picrosirius red staining as compared to & CIII-11C treated mice in both treatment modalities. There was a corresponding decrease in urinary markers including KIM-1, MCP-1, IL-6, NGAL and microalbumin in pUR4 treated mice in both the models. Levels of collagen 1, α-SMA and CTGF were significantly reduced in pUR4 treated mice in both the models. In kidney organoids, pUR4 treatment diminished fibrilogenesis and accumulation of fibronectin and collagen after repetitive cisplatin injury induced fibrosis.

Conclusion


In the current study, we demonstrated that blocking fibronectin fibrillogenesis halts progression of kidney disease in experimental models of kidney fibrosis. Thus, interfering with the FN polymerization may offer a new therapeutic strategy for treating kidney fibrosis

Funding

  • NIDDK Support