PMID- 25961459
OWN - NLM
STAT- MEDLINE
DCOM- 20150812
LR  - 20211203
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 125
IP  - 6
DP  - 2015 Jun
TI  - Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney 
      disease.
PG  - 2399-412
LID - 80467 [pii]
LID - 10.1172/JCI80467 [doi]
AB  - 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-alpha. TNF-alpha induced MIF expression, and MIF subsequently 
      exacerbated TNF-alpha expression in renal epithelial cells, suggesting a positive 
      feedback loop between TNF-alpha 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.
FAU - Chen, Li
AU  - Chen L
FAU - Zhou, Xia
AU  - Zhou X
FAU - Fan, Lucy X
AU  - Fan LX
FAU - Yao, Ying
AU  - Yao Y
FAU - Swenson-Fields, Katherine I
AU  - Swenson-Fields KI
FAU - Gadjeva, Mihaela
AU  - Gadjeva M
FAU - Wallace, Darren P
AU  - Wallace DP
FAU - Peters, Dorien J M
AU  - Peters DJ
FAU - Yu, Alan
AU  - Yu A
FAU - Grantham, Jared J
AU  - Grantham JJ
FAU - Li, Xiaogang
AU  - Li X
LA  - eng
GR  - U01 GM094627/GM/NIGMS NIH HHS/United States
GR  - R01DK081579/DK/NIDDK NIH HHS/United States
GR  - U01GM094627/GM/NIGMS NIH HHS/United States
GR  - P30 DK079310/DK/NIDDK NIH HHS/United States
GR  - R01DK084097/DK/NIDDK NIH HHS/United States
GR  - P30 DK079328/DK/NIDDK NIH HHS/United States
GR  - T32DK071496/DK/NIDDK NIH HHS/United States
GR  - P30DK079328/DK/NIDDK NIH HHS/United States
GR  - R01 DK084097/DK/NIDDK NIH HHS/United States
GR  - R01 DK081579/DK/NIDDK NIH HHS/United States
GR  - R01EY022054/EY/NEI NIH HHS/United States
GR  - T32 DK071496/DK/NIDDK NIH HHS/United States
GR  - R01 EY022054/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150511
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (CCL2 protein, human)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Macrophage Migration-Inhibitory Factors)
RN  - 0 (TRPP Cation Channels)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (polycystic kidney disease 1 protein)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 5.3.- (Intramolecular Oxidoreductases)
RN  - EC 5.3.2.1 (MIF protein, human)
RN  - EC 5.3.2.1 (Mif protein, mouse)
SB  - IM
CIN - Nat Rev Nephrol. 2015 Jul;11(7):388. PMID: 26008714
MH  - Animals
MH  - Cell Line
MH  - Chemokine CCL2/genetics/metabolism
MH  - Disease Models, Animal
MH  - Epithelial Cells/*metabolism/pathology
MH  - Extracellular Signal-Regulated MAP Kinases/genetics/metabolism
MH  - Female
MH  - Gene Expression Regulation/genetics
MH  - Humans
MH  - Intramolecular Oxidoreductases/genetics/*metabolism
MH  - MAP Kinase Signaling System/genetics
MH  - Macrophage Migration-Inhibitory Factors/genetics/*metabolism
MH  - Macrophages/*metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Polycystic Kidney, Autosomal Dominant/genetics/*metabolism/pathology
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
MH  - TRPP Cation Channels/genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/biosynthesis/genetics
PMC - PMC4497763
EDAT- 2015/05/12 06:00
MHDA- 2015/08/13 06:00
PMCR- 2015/09/01
CRDT- 2015/05/12 06:00
PHST- 2014/12/11 00:00 [received]
PHST- 2015/04/06 00:00 [accepted]
PHST- 2015/05/12 06:00 [entrez]
PHST- 2015/05/12 06:00 [pubmed]
PHST- 2015/08/13 06:00 [medline]
PHST- 2015/09/01 00:00 [pmc-release]
AID - 80467 [pii]
AID - 10.1172/JCI80467 [doi]
PST - ppublish
SO  - J Clin Invest. 2015 Jun;125(6):2399-412. doi: 10.1172/JCI80467. Epub 2015 May 11.