Dysregulated ferritin and iron homeostasis in autosomal dominant polycystic kidney disease

Ferritin dysregulation is implicated in numerous pathological conditions; however, its role in autosomal dominant polycystic kidney disease (PKD) remains poorly understood. Ferritin expression is increased in cyst-lining epithelial cells and macrophages in both PKD mouse and human kidneys. To investigate the functional significance of ferritin/iron homeostasis in disease progression, we generated conditional knockout of ferritin heavy chain (FTH) in collecting duct or myeloid lineage cells of PKD mice. FTH deletion in either cell type did not impact renal cyst growth. Notably, loss of FTH expression was accompanied by compensatory upregulation of ferritin light chain (FTL) in both models. To assess the effects of systemic ferritin infusion, we administered ferritin (iron replete), apoferritin (iron deplete), or phosphate-buffered saline (PBS; vehicle control) to PKD mice. Ferritin but not apoferritin infusion led to splenomegaly in wild-type (WT) and PKD mice, with no obvious alterations in cyst progression. Notably, ferritin infusion led to focal accumulation of ferritin in macrophage-enriched regions within the kidneys of PKD, but not WT mice. Consistent with this, elevated iron was detected in the kidneys of ferritin-treated PKD mice but not in wild-type controls, suggesting dysfunctional ferritin trafficking. Mechanistically, we observed increased uptake of ferritin and dysregulation of ferritin receptors by renal cystic epithelial cells of PKD patients. Ferritin-enriched areas were positive for heme oxygenase 1 and represented high oxidative stress and fibrosis. Collectively, these findings demonstrate a disruption in ferritin handling and iron homeostasis in PKD. This altered iron trafficking promotes localized oxidative stress and fibrosis, contributing to disease progression.NEW & NOTEWORTHY Ferritin dysregulation in autosomal dominant polycystic kidney disease (ADPKD) reveals a novel disease mechanism. Although ferritin heavy chain deletion does not affect cyst growth, polycystic kidney disease (PKD) kidneys show compensatory ferritin light chain upregulation and abnormal ferritin trafficking. Iron-loaded ferritin accumulates in macrophage-rich regions, increasing oxidative stress and fibrosis. Enhanced ferritin uptake and receptor dysregulation in cystic epithelial cells highlight disrupted iron homeostasis as a previously unrecognized contributor to ADPKD progression.