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Kidney Week

Abstract: TH-PO984

Effects of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors on Copper Metabolism and Association with Organ Damage in CKD

Session Information

Category: Anemia and Iron Metabolism

  • 200 Anemia and Iron Metabolism

Authors

  • Moriyama, Tomofumi, Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
  • Taguchi, Kensei, Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
  • Kodama, Goh, Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
  • Fukami, Kei, Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
Background

Excess copper accumulates in visceral organs throughout the body producing reactive oxygen species which ultimately causes organ damage. In patients with chronic kidney disease (CKD), excess copper accumulation is known to be a risk factor for worsening renal function. HIF-PhD inhibitors are recently used to treat renal anemia worldwide. Several studies have demonstrated that HIF-PhD inhibitors affect iron kinetics. Meanwhile, there are few reports on copper metabolism. In the present study, we investigated whether HIF-PhD inhibition has an impact on copper metabolism in CKD rodents model and patients with CKD or patients with peritoneal dialysis (PD).

Methods

7 patients with advanced CKD and 9 patients with PD were enrolled in the present study. Serum copper, iron, and zinc were evaluated before and 3 months after the initiation of HIF-PHD inhibitors. In vitro, CuSO4 was administered to cultured proximal tubules to explore whether excess cooper accumulation causes cellular damage. In vivo experiments, GSK360A, a HIF-PHD inhibitor, GSK360A plus HIF-1α inhibitor, or GSK360A plus HIF-2α inhibitor were injected into C57BL/6J mice after induction of CKD by repeated low dose cisplatin injections to examine which HIF compartment is involved in cooper metabolism.

Results

Serum copper was elevated after the treatment with HIF-PhD inhibitors in patients with advanced CKD (104±5→131±24 μg/dL) and PD (101±15→148±20 μg/dL). Meanwhile, serum iron and zinc concentration were not affected by HIF-PhD inhibitors. In vitro experiment, co-incubation with CuSO4 increased α-SMA and cleaved caspase3, suggesting that excess cooper causes fibrotic pathway and ultimately cell death. In vivo experiment, serum copper was elevated in CKD rodents when compared to control, which was further enhanced by treatment with GSK360A. Pharmacological inhibition of HIF-1α did not affect GSK360A-induced increase in copper accumulation, suggesting that HIF-2α might be involved in copper metabolism in response to HIF-PhD treatment.

Conclusion

Copper accumulation can be induced by HIF-PhD inhibitors which might be associated with renal fibrosis and cell death. HIF-2α might mediate copper metabolism in response to HIF-PhD inhibitors.