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Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease
Li Chen, … , Jared J. Grantham, Xiaogang Li
Li Chen, … , Jared J. Grantham, Xiaogang Li
Published May 11, 2015
Citation Information: J Clin Invest. 2015;125(6):2399-2412. https://doi.org/10.1172/JCI80467.
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Research Article Nephrology Article has an altmetric score of 6

Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal cyst formation, inflammation, and fibrosis. Macrophages infiltrate cystic kidneys, but the role of these and other inflammatory factors in disease progression are poorly understood. Here, we identified macrophage migration inhibitory factor (MIF) as an important regulator of cyst growth in ADPKD. MIF was upregulated in cyst-lining epithelial cells in polycystin-1–deficient murine kidneys and accumulated in cyst fluid of human ADPKD kidneys. MIF promoted cystic epithelial cell proliferation by activating ERK, mTOR, and Rb/E2F pathways and by increasing glucose uptake and ATP production, which inhibited AMP-activated protein kinase signaling. MIF also regulated cystic renal epithelial cell apoptosis through p53-dependent signaling. In polycystin-1–deficient mice, MIF was required for recruitment and retention of renal macrophages, which promoted cyst expansion, and Mif deletion or pharmacologic inhibition delayed cyst growth in multiple murine ADPKD models. MIF-dependent macrophage recruitment was associated with upregulation of monocyte chemotactic protein 1 (MCP-1) and inflammatory cytokine TNF-α. TNF-α induced MIF expression, and MIF subsequently exacerbated TNF-α expression in renal epithelial cells, suggesting a positive feedback loop between TNF-α and MIF during cyst development. Our study indicates MIF is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for further exploration of MIF as a therapeutic target for ADPKD.

Authors

Li Chen, Xia Zhou, Lucy X. Fan, Ying Yao, Katherine I. Swenson-Fields, Mihaela Gadjeva, Darren P. Wallace, Dorien J.M. Peters, Alan Yu, Jared J. Grantham, Xiaogang Li

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Figure 1

Pkd1 mutant renal epithelial cells and tissues demonstrated increased expression of MIF.

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Pkd1 mutant renal epithelial cells and tissues demonstrated increased e...
(A) Western blot analysis of the expression of MIF from whole-cell lysates of Pkd1 (WT) and Pkd1null/null (Null) MEK cells, as well as in postnatal Pkd1 heterozygous PH2 (PH2) cells and Pkd1 homozygous PN24 (PN24) cells. The expression of MIF was quantified from 3 independent immunoblots and was presented as the relative expression level of MIF standardized to actin in the bottom panel. P < 0.01. (B) qRT-PCR analysis of the expression of Mif mRNA in Pkd1 (WT) and Pkd1null/null (Null) MEK cells (P < 0.05), as well as in postnatal Pkd1 heterozygous PH2 (PH2) cells and Pkd1 homozygous PN24 (PN24) cells (P < 0.01). n = 3. (C) qRT-PCR analysis of the expression of Mif mRNA in PN7 kidneys from Pkd1+/+ Ksp-Cre (WT) and Pkd1fl/fl Ksp-Cre (Flox) neonates (left panel) (P < 0.05) and in PN25 kidneys from Pkd1+/+ Pkhd1-Cre (WT) and Pkd1fl/fl Pkhd1-Cre (Flox) mice (right panel) (P < 0.05). n = 3. Statistical analysis was performed using an unpaired 2-tailed Student’s t test. (D–F) MIF expression was increased in Pkd1 mutant kidney tissues as examined by immunohistochemical staining with anti-MIF antibody in PN7 kidney sections from Pkd1+/+ Ksp-Cre and Pkd1fl/fl Ksp-Cre neonates (D), in PN25 kidney sections from Pkd1+/+ Pkhd1-Cre and Pkd1fl/fl Pkhd1-Cre mice (E), as well as in kidney sections from normal and ADPKD kidneys (F). Scale bars: 100 μm.

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