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Abstract: FR-PO104

Reduction of Excess Renal Iron Acquisition Diminishes Tubular Injury in Experimental Focal Segmental Glomerulosclerosis

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Van swelm, Rachel, Radboud University Medical Centre, Nijmegen, Netherlands
  • Beurskens, Sanne, Radboud University Medical Center, Nijmegen, Netherlands
  • Dijkman, Henry, Radboud University Medical Center, Nijmegen, Netherlands
  • Wetzels, Jack F., Radboud University Medical Center, Nijmegen, Netherlands
  • Wiegerinck, Erwin, Radboud University Medical Center, Nijmegen, Netherlands
  • Roelofs, Rian, Radboud University Medical Center, Nijmegen, Netherlands
  • Van der vlag, Johan, Radboud University Medical Center, Nijmegen, Netherlands
  • Smeets, Bart, Radboud University Medical Center, Nijmegen, Netherlands
  • Swinkels, Dorine W., Radboud University Medical Center, Nijmegen, Netherlands
Background

Renal iron accumulation as a result of proteinuria is suggested to play a role in progression of chronic kidney disease (CKD). Here, we studied the molecular mechanisms of renal iron loading in experimental focal segmental glomerulosclerosis (FSGS; Thy-1.1 mouse model) and investigated if reduction in renal iron loading decreased tubular injury.

Methods

Thy-1.1 mice were injected with a monoclonal anti-Thy-1.1 antibody (mAb) or saline as control and sacrificed immediately after injection (D1), day 8 (D8) or day 22 (D22).

Results

Injection of mAb resulted in immediate and persistent albuminuria (p<0.01). Renal injury in mAb-injected mice was confirmed by standard histology, increased urinary kidney injury markers KIM1 (p<0.05) and NGAL (p<0.01) and elevated renal mRNA expression of IL-6 (p<0.001) and HO-1 (p<0.01). Increased distal tubular iron accumulation was observed with increasing renal injury in mAb-treated mice. QPCR analysis indicated distal iron accumulation via the NGALR and not transferrin receptor-1 (TfR1). In vivo silencing of renal NGALR resulted in significantly reduced HO-1 and L-ferritin mRNA levels at D8 (both p<0.05), indicating reduced iron accumulation and injury. Systemic iron depletion by iron-deficient diet reduced renal iron accumulation and urinary KIM1 and NGAL on D8 (both p<0.05), but not D22. Interestingly, the iron-deficient diet did not reduce renal IL-6 mRNA, whereas an iron-rich diet diminished IL-6 (D22, p<0.001) and urinary KIM1 (p<0.05) and NGAL (p<0.001) on D8 and D22, despite concurrent increased iron deposition and oxidative stress as indicated by HO-1 immunostaining and mRNA expression (p<0.001). Alternatively, we aimed to prevent excess renal iron deposition by reducing glomerular protein filtration (captopril; CA) or iron chelation (deferoxamine; DFO) for 7 days after mAb injection. Both CA and DFO reduced renal iron accumulation, and urinary KIM1 and NGAL (p<0.05) on D8, which did not last until D22, suggesting requirement for continuous treatment.

Conclusion

In conclusion, our results indicate that prevention of excess renal iron accumulation could be useful to halt progression of tubular injury in CKD. However, disturbances in systemic iron balance are not feasible, warranting a targeted renal approach.

Funding

  • Private Foundation Support