期刊
KIDNEY INTERNATIONAL
卷 88, 期 1, 页码 95-108出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2015.102
关键词
acute kidney injury; ferritin; fibrosis; inflammation; macrophage polarization
资金
- NIH [P30 AR048311, P30 AI027767, R01 DK59600]
- Fundacao para a Ciencia e Tecnologia [PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010]
- European Union [ERC-2011-AdG. 294709 DAMAGECONTROL]
- AHA Grant [11POST7600074]
- UAB-UCSD O'Brien Center [P30 DK079337, R01 DK083390]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-TOX/116627/2010] Funding Source: FCT
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.
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