PMID- 27482889
OWN - NLM
STAT- MEDLINE
DCOM- 20170926
LR  - 20181113
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 126
IP  - 9
DP  - 2016 Sep 1
TI  - Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury.
PG  - 3336-50
LID - 85939 [pii]
LID - 10.1172/JCI85939 [doi]
AB  - High levels of circulating TNF and its receptors, TNFR1 and TNFR2, predict the 
      progression of diabetic kidney disease (DKD), but their contribution to organ 
      damage in DKD remains largely unknown. Here, we investigated the function of 
      local and systemic TNF in podocyte injury. We cultured human podocytes with sera 
      collected from DKD patients, who displayed elevated TNF levels, and focal 
      segmental glomerulosclerosis (FSGS) patients, whose TNF levels resembled those of 
      healthy patients. Exogenous TNF administration or local TNF expression was 
      equally sufficient to cause free cholesterol-dependent apoptosis in podocytes by 
      acting through a dual mechanism that required a reduction in ATP-binding cassette 
      transporter A1-mediated (ABCA1-mediated) cholesterol efflux and reduced 
      cholesterol esterification by sterol-O-acyltransferase 1 (SOAT1). TNF-induced 
      albuminuria was aggravated in mice with podocyte-specific ABCA1 deficiency and 
      was partially prevented by cholesterol depletion with cyclodextrin. 
      TNF-stimulated free cholesterol-dependent apoptosis in podocytes was mediated by 
      nuclear factor of activated T cells 1 (NFATc1). ABCA1 overexpression or 
      cholesterol depletion was sufficient to reduce albuminuria in mice with 
      podocyte-specific NFATc1 activation. Our data implicate an NFATc1/ABCA1-dependent 
      mechanism in which local TNF is sufficient to cause free cholesterol-dependent 
      podocyte injury irrespective of TNF, TNFR1, or TNFR2 serum levels.
FAU - Pedigo, Christopher E
AU  - Pedigo CE
FAU - Ducasa, Gloria Michelle
AU  - Ducasa GM
FAU - Leclercq, Farah
AU  - Leclercq F
FAU - Sloan, Alexis
AU  - Sloan A
FAU - Mitrofanova, Alla
AU  - Mitrofanova A
FAU - Hashmi, Tahreem
AU  - Hashmi T
FAU - Molina-David, Judith
AU  - Molina-David J
FAU - Ge, Mengyuan
AU  - Ge M
FAU - Lassenius, Mariann I
AU  - Lassenius MI
FAU - Forsblom, Carol
AU  - Forsblom C
FAU - Lehto, Markku
AU  - Lehto M
FAU - Groop, Per-Henrik
AU  - Groop PH
FAU - Kretzler, Matthias
AU  - Kretzler M
FAU - Eddy, Sean
AU  - Eddy S
FAU - Martini, Sebastian
AU  - Martini S
FAU - Reich, Heather
AU  - Reich H
FAU - Wahl, Patricia
AU  - Wahl P
FAU - Ghiggeri, GianMarco
AU  - Ghiggeri G
FAU - Faul, Christian
AU  - Faul C
FAU - Burke, George W 3rd
AU  - Burke GW 3rd
FAU - Kretz, Oliver
AU  - Kretz O
FAU - Huber, Tobias B
AU  - Huber TB
FAU - Mendez, Armando J
AU  - Mendez AJ
FAU - Merscher, Sandra
AU  - Merscher S
FAU - Fornoni, Alessia
AU  - Fornoni A
LA  - eng
GR  - U24 DK076169/DK/NIDDK NIH HHS/United States
GR  - U54 DK083912/DK/NIDDK NIH HHS/United States
GR  - R01 DK104753/DK/NIDDK NIH HHS/United States
GR  - UM1 DK100846/DK/NIDDK NIH HHS/United States
GR  - UL1 TR000460/TR/NCATS NIH HHS/United States
GR  - R01 HL128714/HL/NHLBI NIH HHS/United States
GR  - P30 DK081943/DK/NIDDK NIH HHS/United States
GR  - R01 DK090316/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160802
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (ABCA1 protein, human)
RN  - 0 (ABCA1 protein, mouse)
RN  - 0 (ATP Binding Cassette Transporter 1)
RN  - 0 (Cyclodextrins)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (NFATC1 protein, human)
RN  - 0 (Nfatc1 protein, mouse)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
RN  - 0 (TNFRSF1A protein, human)
RN  - 0 (TNFRSF1B protein, human)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.3.1.26 (Sterol O-Acyltransferase)
RN  - EC 2.3.1.26 (sterol O-acyltransferase 1)
SB  - IM
MH  - ATP Binding Cassette Transporter 1/physiology
MH  - Adolescent
MH  - Albuminuria/blood
MH  - Animals
MH  - Apoptosis
MH  - Biopsy
MH  - Case-Control Studies
MH  - Child
MH  - Child, Preschool
MH  - Cholesterol/*chemistry
MH  - Cyclodextrins/metabolism
MH  - Diabetic Nephropathies/*blood
MH  - Female
MH  - Gene Expression Regulation
MH  - Glomerular Filtration Rate
MH  - Glomerulosclerosis, Focal Segmental/*blood
MH  - Humans
MH  - Inflammation
MH  - Kidney/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - NFATC Transcription Factors/*physiology
MH  - Nephrotic Syndrome/*blood
MH  - Podocytes/metabolism
MH  - Receptors, Tumor Necrosis Factor, Type I/blood
MH  - Receptors, Tumor Necrosis Factor, Type II/blood
MH  - Sterol O-Acyltransferase/physiology
MH  - Tumor Necrosis Factor-alpha/pharmacology/*physiology
PMC - PMC5004940
EDAT- 2016/08/03 06:00
MHDA- 2017/09/28 06:00
PMCR- 2016/12/01
CRDT- 2016/08/03 06:00
PHST- 2015/12/14 00:00 [received]
PHST- 2016/05/26 00:00 [accepted]
PHST- 2016/08/03 06:00 [entrez]
PHST- 2016/08/03 06:00 [pubmed]
PHST- 2017/09/28 06:00 [medline]
PHST- 2016/12/01 00:00 [pmc-release]
AID - 85939 [pii]
AID - 10.1172/JCI85939 [doi]
PST - ppublish
SO  - J Clin Invest. 2016 Sep 1;126(9):3336-50. doi: 10.1172/JCI85939. Epub 2016 Aug 2.