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Abstract: TH-PO918

Inhibition of Fibronectin Polymerization Attenuates Ischemia-Induced Kidney Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Bowers, Stephanie L.K., Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • Davis, Stephanie, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • Rudomanova, Valeriia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • Ma, Qing, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • Devarajan, Prasad, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • Blaxall, Burns C., Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Background

Fibrosis is a hallmark of chronic kidney disease (CKD), regardless of pathophysiologic origin. After injury, activation of tissue fibroblasts leads to increased extracellular matrix (ECM) deposition and adverse tissue remodeling. Fibronectin (FN) is a vital component of the ECM that orchestrates the composition and organization of numerous matrix and cell surface proteins. The current study tested the hypothesis that treatment with the peptide pUR4, which inhibits cell-mediated FN polymerization, would mitigate ischemia-induced tissue remodeling and preserve renal morphology.

Methods

A mouse model of unilateral ischemia/reperfusion (UIR) injury was created by placement of an atraumatic clamp on the left renal artery for 30 minutes, followed by 14 days of reperfusion. Daily IP injections of pUR4 (25mg/kg), control inactive peptide (III-11C; 25mg/kg) or PBS were started on the same day (concomitant), or 7-days post-UIR (delayed). After 14 days, mice were sacrificed and both the left (injured) and right (uninjured) kidneys were collected; animals were assessed for evidence of injury by histology and immunofluorescence.

Results

Inhibition of FN polymerization with delayed (but not with concomitant) pUR4 treatment decreased renal FN expression and deposition following UIR (1.0 (III-11C) vs. 0.56 (pUR4), p=0.01, n=4 each). Delayed pUR4 administration alleviated the characteristic UIR-induced decrease in kidney weight (5.4 vs. 6.5mg/kg body weight, p=0.009; n=12 for III-11C, n=14 for pUR4). Moreover, delayed pUR4 decreased cortical fibrosis (by picrosirius Red staining) compared to III-11C (12.1 vs. 6.0%, p=0.0009, n=12 or 14, respectively) but not medullary fibrosis (20.2 vs. 14.4%, p=0.18). Histologic evaluation also revealed preserved tubule morphology with delayed pUR4 treatment.

Conclusion

Collectively, these experiments provide evidence that decreasing FN polymerization may attenuate the progression of CKD following renal ischemic injury.

Funding

  • Other NIH Support