Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease
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
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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Research Article Nephrology

Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

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 8

A schematic diagram depicting MIF-mediated pathways and processes in Pkd1 mutant renal epithelial cells.

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A schematic diagram depicting MIF-mediated pathways and processes in Pkd...
Pkd1 KO or mutation results in the upregulation of MIF, which may be stabilized via HSP90, induced by cyst fluid TNF-α or through another unknown mechanism. Upregulated MIF in Pkd1 mutant renal epithelial cells activates ERK and mTOR signaling, which may result in activation of ERK-mTOR–mediated cell proliferation and glycolysis, as has been suggested. It also increases glucose uptake, which results in promoting glycolysis and the generation of ATP to inhibit AMPK; inhibits p53-dependent cystic epithelial cell death; is responsible for the recruitment of macrophages to pericystic and interstitial regions in Pkd1 mutant mouse kidneys, a process likely to be enhanced by MIF-mediated upregulation of MCP-1 and/or TNF-α; and is a target of ISO-1, which delays cyst growth in Pkd1 KO mouse kidneys. In addition, 2 double-negative feedback loops downstream of MIF can be observed: among ERK-mTOR-glycolysis-AMPK-ERK and among mTOR-glycolysis-AMPK-mTOR. Arrow indicates the positive effect; “T” indicates the negative effect. Dashed lines indicate putative signaling mechanisms.