PMID- 29724730
OWN - NLM
STAT- MEDLINE
DCOM- 20190805
LR  - 20200701
IS  - 1468-2060 (Electronic)
IS  - 0003-4967 (Print)
IS  - 0003-4967 (Linking)
VI  - 77
IP  - 8
DP  - 2018 Aug
TI  - Metabolic pathways and immunometabolism in rare kidney diseases.
PG  - 1226-1233
LID - 10.1136/annrheumdis-2017-212935 [doi]
AB  - OBJECTIVES: To characterise renal tissue metabolic pathway gene expression in 
      different forms of glomerulonephritis. METHODS: Patients with nephrotic syndrome 
      (NS), antineutrophil cytoplasmic antibody-associated vasculitis (AAV), systemic 
      lupus erythematosus (SLE) and healthy living donors (LD) were studied. Clinically 
      indicated renal biopsies were obtained at time of diagnosis and microdissected 
      into glomerular and tubulointerstitial compartments. Microarray-derived 
      differential gene expression of 88 genes representing critical enzymes of 
      metabolic pathways and 25 genes related to immune cell markers was compared 
      between disease groups. Correlation analyses measured relationships between 
      metabolic pathways, kidney function and cytokine production. RESULTS: Reduced 
      steady state levels of mRNA species were enriched in pathways of oxidative 
      phosphorylation and increased in the pentose phosphate pathway (PPP) with maximal 
      perturbation in AAV and SLE followed by NS, and least in LD. Transcript 
      regulation was isozymes specific with robust regulation in hexokinases, enolases 
      and glucose transporters. Intercorrelation networks were observed between enzymes 
      of the PPP (eg, transketolase) and macrophage markers (eg, CD68) (r=0.49, 
      p<0.01). Increased PPP transcript levels were associated with reduced glomerular 
      filtration rate in the glomerular (r=-0.49, p<0.01) and tubulointerstitial 
      (r=-0.41, p<0.01) compartments. PPP expression and tumour necrosis factor 
      activation were tightly co-expressed (r=0.70, p<0.01). CONCLUSION: This study 
      demonstrated concordant alterations of the renal transcriptome consistent with 
      metabolic reprogramming across different forms of glomerulonephritis. Activation 
      of the PPP was tightly linked with intrarenal macrophage marker expression, 
      reduced kidney function and increased production of cytokines. Modulation of 
      glucose metabolism may offer novel immune-modulatory therapeutic approaches in 
      rare kidney diseases.
CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text of 
      the article) 2018. All rights reserved. No commercial use is permitted unless 
      otherwise expressly granted.
FAU - Grayson, Peter C
AU  - Grayson PC
AD  - Vasculitis Translational Research Program, Systemic Autoimmunity Branch, National 
      Institutes of Health/NIAMS, Bethesda, Maryland, USA.
AD  - Vasculitis Clinical Research Consortium, Philadelphia, Pennsylvania, USA.
FAU - Eddy, Sean
AU  - Eddy S
AD  - Division of Nephrology, Michigan Medicine, University of Michigan, Ann Arbor, 
      Michigan, USA.
AD  - Nephrotic Syndrome Study Network Consortia, Ann Arbor, Michigan, USA.
FAU - Taroni, Jaclyn N
AU  - Taroni JN
AD  - Vasculitis Clinical Research Consortium, Philadelphia, Pennsylvania, USA.
AD  - Department of Systems Pharmacology and Translational Therapeutics, Institute for 
      Translational Medicine and Therapeutics, Institute for Biomedical Informatics, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, 
      Pennsylvania, USA.
FAU - Lightfoot, Yaima L
AU  - Lightfoot YL
AD  - Vasculitis Translational Research Program, Systemic Autoimmunity Branch, National 
      Institutes of Health/NIAMS, Bethesda, Maryland, USA.
FAU - Mariani, Laura
AU  - Mariani L
AD  - Division of Nephrology, Michigan Medicine, University of Michigan, Ann Arbor, 
      Michigan, USA.
AD  - Nephrotic Syndrome Study Network Consortia, Ann Arbor, Michigan, USA.
FAU - Parikh, Hemang
AU  - Parikh H
AD  - Vasculitis Clinical Research Consortium, Philadelphia, Pennsylvania, USA.
AD  - Health Informatics Institute, Morsani College of Medicine, University of South 
      Florida, Tampa, Florida, USA.
FAU - Lindenmeyer, Maja T
AU  - Lindenmeyer MT
AD  - Nephrological Center Medical Clinic and Polyclinic IV, University of Munich, 
      Munich, Germany.
FAU - Ju, Wenjun
AU  - Ju W
AD  - Division of Nephrology, Michigan Medicine, University of Michigan, Ann Arbor, 
      Michigan, USA.
AD  - Nephrotic Syndrome Study Network Consortia, Ann Arbor, Michigan, USA.
FAU - Greene, Casey S
AU  - Greene CS
AD  - Vasculitis Clinical Research Consortium, Philadelphia, Pennsylvania, USA.
AD  - Department of Systems Pharmacology and Translational Therapeutics, Institute for 
      Translational Medicine and Therapeutics, Institute for Biomedical Informatics, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, 
      Pennsylvania, USA.
FAU - Godfrey, Brad
AU  - Godfrey B
AD  - Division of Nephrology, Michigan Medicine, University of Michigan, Ann Arbor, 
      Michigan, USA.
AD  - Nephrotic Syndrome Study Network Consortia, Ann Arbor, Michigan, USA.
FAU - Cohen, Clemens D
AU  - Cohen CD
AD  - Nephrological Center Medical Clinic and Polyclinic IV, University of Munich, 
      Munich, Germany.
FAU - Krischer, Jeffrey
AU  - Krischer J
AD  - Vasculitis Clinical Research Consortium, Philadelphia, Pennsylvania, USA.
AD  - Health Informatics Institute, Morsani College of Medicine, University of South 
      Florida, Tampa, Florida, USA.
FAU - Kretzler, Matthias
AU  - Kretzler M
AD  - Division of Nephrology, Michigan Medicine, University of Michigan, Ann Arbor, 
      Michigan, USA.
AD  - Nephrotic Syndrome Study Network Consortia, Ann Arbor, Michigan, USA.
FAU - Merkel, Peter A
AU  - Merkel PA
AD  - Vasculitis Clinical Research Consortium, Philadelphia, Pennsylvania, USA.
AD  - Division of Rheumatology and Department of Biostatistics, Epidemiology, and 
      Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
CN  - Vasculitis Clinical Research Consortium, the European Renal cDNA Bank cohort, and 
      the Nephrotic Syndrome Study Network
LA  - eng
GR  - U54 DK083912/DK/NIDDK NIH HHS/United States
GR  - U54 RR019497/RR/NCRR NIH HHS/United States
GR  - T32 AR007442/AR/NIAMS NIH HHS/United States
GR  - P30 DK081943/DK/NIDDK NIH HHS/United States
GR  - U54 AR057319/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180503
PL  - England
TA  - Ann Rheum Dis
JT  - Annals of the rheumatic diseases
JID - 0372355
RN  - 0 (Cytokines)
RN  - 0 (Isoenzymes)
RN  - 0 (RNA, Messenger)
MH  - Adult
MH  - Aged
MH  - Anti-Neutrophil Cytoplasmic Antibody-Associated 
      Vasculitis/genetics/metabolism/pathology
MH  - Biopsy
MH  - Cytokines/biosynthesis
MH  - Female
MH  - Gene Expression Regulation
MH  - Glomerulonephritis/genetics/*metabolism/pathology
MH  - Humans
MH  - Isoenzymes/metabolism
MH  - Kidney Glomerulus/metabolism/pathology
MH  - Kidney Tubules/metabolism/pathology
MH  - Lupus Erythematosus, Systemic/genetics/metabolism/pathology
MH  - Male
MH  - Metabolic Networks and Pathways/*genetics/immunology
MH  - Middle Aged
MH  - Nephrotic Syndrome/genetics/metabolism/pathology
MH  - Pentose Phosphate Pathway/genetics
MH  - RNA, Messenger/genetics
MH  - Transcriptome
MH  - Young Adult
PMC - PMC6045442
MID - NIHMS975677
OTO - NOTNLM
OT  - granulomatosis with polyangiitis
OT  - lupus nephritis
OT  - systemic vasculitis
COIS- Competing interests: None declared.
EDAT- 2018/05/05 06:00
MHDA- 2019/08/06 06:00
PMCR- 2018/08/01
CRDT- 2018/05/05 06:00
PHST- 2017/12/31 00:00 [received]
PHST- 2018/04/04 00:00 [revised]
PHST- 2018/04/16 00:00 [accepted]
PHST- 2018/05/05 06:00 [pubmed]
PHST- 2019/08/06 06:00 [medline]
PHST- 2018/05/05 06:00 [entrez]
PHST- 2018/08/01 00:00 [pmc-release]
AID - annrheumdis-2017-212935 [pii]
AID - 10.1136/annrheumdis-2017-212935 [doi]
PST - ppublish
SO  - Ann Rheum Dis. 2018 Aug;77(8):1226-1233. doi: 10.1136/annrheumdis-2017-212935. 
      Epub 2018 May 3.