Macrophage and epithelial cell H-ferritin expression regulates renal inflammation

Inflammation culminating in fibrosis contributes to progressive kidney disease. Cross-talk between the tubular epithelium and interstitial cells regulates inflammation by a coordinated release of cytokines and chemokines. Here we studied the role of heme oxygenase-1 (HO-1) and the heavy subunit of ferritin (FtH) in macrophage polarization and renal inflammation. Deficiency in HO-1 was associated with increased FtH expression, accumulation of macrophages with a dysregulated polarization profile, and increased fibrosis following unilateral ureteral obstruction in mice: a model of renal inflammation and fibrosis. Macrophage polarization in vitro was predominantly dependent on FtH expression in isolated bone marrow-derived mouse monocytes. Using transgenic mice with conditional deletion of FtH in the proximal tubules (FtH(PT-/-)) or myeloid cells (FtH(LysM-/-)), we found that myeloid FtH deficiency did not affect polarization or accumulation of macrophages in the injured kidney compared with wild-type (FtH(+/+)) controls. However, tubular FtH deletion led to a marked increase in proinflammatory macrophages. Furthermore, injured kidneys from FtH(PT-/-) mice expressed significantly higher levels of inflammatory chemokines and fibrosis compared with kidneys from FtH(+/+) and FtH(LysM-/-) mice. Thus, there are differential effects of FtH in macrophages and epithelial cells, which underscore the critical role of FtH in tubular-macrophage cross-talk during kidney injury.

Description

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Keywords

Animals Apoferritins Cells, Cultured Chemokine CCL2 Disease Models, Animal Epithelial Cells Fibrosis Gene Expression Heme Oxygenase-1 Interleukin-10 Interleukin-6 Kidney Kidney Tubules, Proximal Macrophage Activation Macrophage Colony-Stimulating Factor Macrophages Male Mice Mice, Inbred C57BL Mice, Transgenic Myeloid Cells Nephritis RNA, Messenger Ureteral Obstruction

URI

http://hdl.handle.net/10400.7/770

Citation

Subhashini Bolisetty, Abolfazl Zarjou, Travis D. Hull, Amie M. Traylor, Anjana Perianayagam, Reny Joseph, Ahmed I. Kamal, Paolo Arosio, Miguel P. Soares, Viktoria Jeney, Jozsef Balla, James F. George, Anupam Agarwal, Macrophage and epithelial cell H-ferritin expression regulates renal inflammation, Kidney International, Volume 88, Issue 1, 2015, Pages 95-108, ISSN 0085-2538, http://dx.doi.org/10.1038/ki.2015.102. (http://www.sciencedirect.com/science/article/pii/S2157171615321183) Keywords: acute kidney injury; ferritin; fibrosis; inflammation; macrophage polarization