title: 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.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Xia
authors.initials: X
authors.lastname: Zhou
authors.forename: Lucy X
authors.initials: LX
authors.lastname: Fan
authors.forename: Ying
authors.initials: Y
authors.lastname: Yao
authors.forename: Katherine I
authors.initials: KI
authors.lastname: Swenson-Fields
authors.forename: Mihaela
authors.initials: M
authors.lastname: Gadjeva
authors.forename: Darren P
authors.initials: DP
authors.lastname: Wallace
authors.forename: Dorien J M
authors.initials: DJ
authors.lastname: Peters
authors.forename: Alan
authors.initials: A
authors.lastname: Yu
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Grantham
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018932:Chemokine CCL2; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels; D014409:Tumor Necrosis Factor-alpha; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C515598:MIF protein, human; C076231:Mif protein, mouse