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Abstract: FR-PO243

Ferritin as an Inflammatory Molecule in Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Dinh Phan, Johnny, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
  • Sommer, Nicole, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
  • Thornton, Mackenzie, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
  • Mcgonigle, Mercedes Bravo, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
  • Bolisetty, Subhashini, The University of Alabama at Birmingham Department of Cell Developmental and Integrative Biology, Birmingham, Alabama, United States
  • Wallace, Darren P., University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
  • Sharma, Madhulika, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
Background

Despite approval of tolvaptan as the first drug in the treatment of autosomal dominant polycystic kidney disease (ADPKD), there is an unmet need for new drugs. We need drugs with greater efficacy and new drug targets that could enhance discovery of novel drugs. We have recently reported that ferritin is ectopically expressed in cyst lining cells and macrophages of ADPKD patients and an orthologous mouse model of PKD. Ferritin has previously been shown to activate the inflammatory NF-kappa B pathway in acute kidney injury. Since ferritin is also an acute phase reactant expressed in macrophages, we determined whether ferritin has an inflammatory role in ADPKD cells.

Methods

We treated primary cyst lining ADPKD and normal kidney epithelial (NHK) cells with ferritin and apoferritin to determine the effects on cell proliferation and inflammatory pathway, MAPK-NF-kappa B. We also studied the effects of ferritin deletion in collecting ducts of PKD mice. We used cell culture and Western blots to study ferritin expression in bone marrow derived macrophages in PKD mice.

Results

We found that cyst lining epithelial from ADPKD patients have increased capacity of extracellular ferritin uptake when compared to normal human kidney cells. Ferritin uptake was associated with increased expression of pERK and phosphorylated p65 (Nuclear factor kappa B (NF-kappa-B p65/RelA), suggesting activation of inflammatory signaling pathways. When we labeled cystic mouse PKD kidneys, we found that macrophages close to the epithelial cells expressed ferritin. We hypothesized that macrophages release ferritin which cyst epithelia cells can uptake to mediate inflammation in ADPKD kidneys. Consistent with that isolated bone marrow derived macrophages of PKD mice showed increased ferritin levels. We also show the effects of ferritin deletion in collecting ducts of a PKD mouse model. Our data suggest that ferritin may mediate a cross talk between cyst epithelial cells and macrophages.

Conclusion

We found that macrophages in the ADPKD kidneys express ferritin. ADPKD cyst lining cells have increased capacity for uptake of ferritin, which results in elevation of inflammatory pathway and may be responsible for aggravation of disease. Thus ferritin inhibition in cyst lining cells may constitute a therapeutic target.

Funding

  • Other NIH Support