Iron Metabolism in Kidney Health and Disease

Iron is indispensable for renal cellular energy production, oxygen transport and enzymatic reactions, yet its redox activity renders the kidney vulnerable to oxidative damage. In healthy physiology, transferrin-bound iron filtered at the glomerulus is reabsorbed by proximal tubular cells via the megalin–cubilin complex and transferrin receptor 1, followed by endosomal ferrireduction and cytosolic transport through divalent metal transporter 1. Intracellular iron is stored safely in ferritin or exported by ferroportin, maintaining a balance that prevents free‐radical generation. In disease states such as acute kidney injury and chronic kidney disease, dysregulation of uptake, storage and export leads to tubular iron accumulation, lipid peroxidation and ferroptosis. Systemic factors, including hepcidin and inflammatory cytokines, further perturb renal iron handling, contributing to fibrosis, decline of glomerular filtration and progression to end-stage renal failure. Understanding these pathways is essential for developing targeted therapies that restore iron homeostasis and preserve renal function.

Research from Nature Portfolio

Analyses of human kidney biopsies have mapped the localisation of key iron importers (ZIP8, ZIP14, DMT1), storage proteins (L- and H-ferritin) and exporters (ferroportin) in proximal and distal tubules, revealing that chronic kidney disease is often accompanied by tubular iron deposition arising from increased uptake and impaired export. This deposition correlates with markers of oxidative injury. In mouse models of protein-overload nephropathy, dietary iron restriction was shown to attenuate tubulointerstitial fibrosis by reducing NADPH oxidase activity, inflammatory cytokine expression and inflammasome activation, thereby highlighting a protective effect of limiting renal iron. A novel engineered form of the siderophore-binding protein lipocalin 2 bypasses proximal tubular recapture to facilitate urinary iron excretion, offering a non-toxic chelation strategy that may prevent renal iron overload without systemic toxicity.

Iron Metabolism in Kidney Health and Disease publication trend

The graph below shows the total number of articles in iron metabolism in kidney health and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Transferrin: plasma glycoprotein that binds Fe³⁺ and delivers it to cells via receptor-mediated endocytosis.

Ferroportin: the sole known cellular iron exporter, regulating iron release into the bloodstream.

Divalent metal transporter 1 (DMT1): membrane protein responsible for uptake of Fe²⁺ from endosomes or the tubular lumen.

Ferritin: intracellular nanocage protein complex that stores iron in a non-reactive form.

Megalin–cubilin complex: apical receptor system in proximal tubular cells that mediates endocytosis of filtered proteins, including transferrin.

Ferroptosis: regulated form of cell death driven by iron-dependent lipid peroxidation and loss of membrane integrity.

References

1. Proximal tubule transferrin uptake is modulated by cellular iron and mediated by apical membrane megalin–cubilin complex and transferrin receptor 1. Journal of Biological Chemistry (2019).
2. Iron uptake by ZIP8 and ZIP14 in human proximal tubular epithelial cells. BioMetals (2019).
3. Tubular iron deposition and iron handling proteins in human healthy kidney and chronic kidney disease. Scientific Reports (2018).
4. Disposal of iron by a mutant form of lipocalin 2. Nature Communications (2016).
5. Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice. Scientific Reports (2017).
6. Iron homeostasis, recycling and vulnerability in the stressed kidney: A neglected dimension of iron‐deficient heart failure. European Journal of Heart Failure (2024).
7. Iron therapy mitigates chronic kidney disease progression by regulating intracellular iron status of kidney macrophages. JCI Insight (2023).
8. Advance in Iron Metabolism, Oxidative Stress and Cellular Dysfunction in Experimental and Human Kidney Diseases. Antioxidants (2024).