Phosphate Binder, Ferric Citrate, Attenuates Anemia, Renal Dysfunction, Oxidative Stress, Inflammation, and Fibrosis in 5/6 Nephrectomized CKD Rats.

Abstract

Chronic kidney disease (CKD) causes anemia and impairs intestinal iron absorption. However, use of the phosphate binder ferric citrate (FC) increases body iron stores and hemoglobin levels in CKD patients. By intensifying oxidative stress and inflammation iron overload resulting from excessive use of intravenous iron can accelerate CKD progression. The present study explored the route of absorption and tissue distribution of iron with FC administration and its effect on renal function, histology, and inflammatory, oxidative, and fibrosis pathways in CKD rats. Male Sprague Dawley rats were randomized to sham-operated control (CTL) group and 5/6 nephrectomized (CKD) groups fed either regular or 4% FC-supplemented diets for 6 weeks. Animals were then sacrificed, and blood and target tissues were harvested and processed. The untreated CKD rats exhibited anemia, hypertension, upregulation of renal tissue inflammatory, oxidative, and fibrotic pathways, impaired nuclear translocation, and downregulation of Nrf2's target gene products and depletion of colonic epithelial tight junction proteins. FC administration raised serum iron, improved anemia, attenuated hyperphosphatemia, partially improved renal function, reduced oxidative stress, inflammation, and fibrosis, and restored colonic epithelial zonula occludens-1 protein abundance. Tissue iron staining detected presence of iron in epithelial cells and subepithelium of colon and in renal proximal tubules. In conclusion ferric citrate administration resulted in modest amelioration of renal function and histology and partial improvements of fibrosis, inflammation, and oxidative stress in the kidney tissues of CKD rats.

• Authors: Wanghui Jing, Ane C F Nunes, Ted Farzaneh, Mahyar Khazaeli, Wei Ling Lau, Nosratola D Vaziri
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 367 Issue 1 Pg. 129-137 (10 2018) ISSN: 1521-0103 [Electronic] United States
• PMID: 30093458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Ferric Compounds
• NF-E2-Related Factor 2
• Phosphates
• Tight Junction Proteins
• Zonula Occludens-1 Protein
• ferric citrate
• Iron

Topics

• Anemia (drug therapy, metabolism)
• Animals
• Colon (drug effects, metabolism)
• Down-Regulation (drug effects)
• Epithelial Cells (drug effects, metabolism)
• Ferric Compounds (pharmacology)
• Fibrosis (drug therapy, metabolism)
• Inflammation (drug therapy, metabolism)
• Iron (metabolism)
• Kidney Tubules, Proximal (drug effects, metabolism)
• Male
• NF-E2-Related Factor 2 (metabolism)
• Nephrectomy (methods)
• Oxidative Stress (drug effects)
• Phosphates (metabolism)
• Rats
• Rats, Sprague-Dawley
• Renal Insufficiency, Chronic (drug therapy, metabolism)
• Tight Junction Proteins (metabolism)
• Up-Regulation (drug effects)
• Zonula Occludens-1 Protein (metabolism)