PMID- 26414003
OWN - NLM
STAT- MEDLINE
DCOM- 20161014
LR  - 20161230
IS  - 1440-1681 (Electronic)
IS  - 0305-1870 (Linking)
VI  - 43
IP  - 1
DP  - 2016 Jan
TI  - Increased sphingosine 1-phosphate mediates inflammation and fibrosis in tubular 
      injury in diabetic nephropathy.
PG  - 56-66
LID - 10.1111/1440-1681.12494 [doi]
AB  - Hyperglycemia induces all isoforms of transforming growth factor beta (TGFbeta), which 
      in turn play key roles in inflammation and fibrosis that characterize diabetic 
      nephropathy. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid, derived 
      from sphingosine by the action of sphingosine kinase (SK). S1P mediates many 
      biological processes, which mimic TGFbeta signaling. To determine the role of SK1 
      and S1P in inducing fibrosis and inflammation, and the interaction with TGFbeta-1, 2 
      and 3 signalling in diabetic nephropathy, human proximal tubular cells (HK2 
      cells) were exposed to normal (5 mmol/L) or high (30 mmol/L) glucose or TGFbeta-1, 
      -2, -3 +/- an SK inhibitor (SKI-II) or SK1 siRNA. Control and diabetic wild type 
      (WT) and SK1(-/-) mice were studied. Fibrotic and inflammatory markers, and 
      relevant downstream signalling pathways were assessed. SK1 mRNA and protein 
      expression was increased in HK2 cells exposed to high glucose or TGFbeta1,-2,-3. All 
      TGFbeta isoforms induced fibronectin, collagen IV and macrophage chemoattractant 
      protein 1 (MCP1), which were reversed by both SKI-II and SK1 siRNA. Exposure to 
      S1P increased phospho-p44/42 expression, AP-1 binding and NFkB phosphorylation. 
      WT diabetic mice exhibited increased renal cortical S1P, fibronectin, collagen IV 
      and MCP1 mRNA and protein expression compared to SK1(-/-) diabetic mice. In 
      summary, this study demonstrates that inhibiting the formation of S1P reduces 
      tubulointerstitial renal inflammation and fibrosis in diabetic nephropathy.
CI  - (c) 2015 Wiley Publishing Asia Pty Ltd.
FAU - Yaghobian, Dania
AU  - Yaghobian D
AD  - Department of Medicine, Kolling Institute of Medical Research, University of 
      Sydney, St. Leonards, New South Wales, Australia.
FAU - Don, Anthony S
AU  - Don AS
AD  - Department of Medicine, Lowy Cancer Research Centre, University of New South 
      Wales, Sydney, New South Wales, Australia.
FAU - Yaghobian, Sarina
AU  - Yaghobian S
AD  - Department of Medicine, Kolling Institute of Medical Research, University of 
      Sydney, St. Leonards, New South Wales, Australia.
FAU - Chen, Xinming
AU  - Chen X
AD  - Department of Medicine, Kolling Institute of Medical Research, University of 
      Sydney, St. Leonards, New South Wales, Australia.
FAU - Pollock, Carol A
AU  - Pollock CA
AD  - Department of Medicine, Kolling Institute of Medical Research, University of 
      Sydney, St. Leonards, New South Wales, Australia.
FAU - Saad, Sonia
AU  - Saad S
AD  - Department of Medicine, Kolling Institute of Medical Research, University of 
      Sydney, St. Leonards, New South Wales, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Australia
TA  - Clin Exp Pharmacol Physiol
JT  - Clinical and experimental pharmacology & physiology
JID - 0425076
RN  - 0 (Biomarkers)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lysophospholipids)
RN  - 0 (NF-kappa B)
RN  - 0 (Phosphoproteins)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Transforming Growth Factor beta)
RN  - 26993-30-6 (sphingosine 1-phosphate)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - IY9XDZ35W2 (Glucose)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
MH  - Animals
MH  - Biomarkers/metabolism
MH  - Cell Line
MH  - Diabetic Nephropathies/enzymology/*metabolism/*pathology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/pharmacology
MH  - Extracellular Matrix/drug effects/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Fibrosis
MH  - Gene Expression Regulation, Enzymologic/drug effects
MH  - Gene Silencing
MH  - Glucose/pharmacology
MH  - Humans
MH  - Inflammation/enzymology/metabolism/pathology
MH  - Kidney Cortex/drug effects/metabolism/pathology
MH  - Kidney Tubules/drug effects/*injuries/*metabolism/pathology
MH  - Lysophospholipids/*metabolism
MH  - Male
MH  - Mice
MH  - NF-kappa B/metabolism
MH  - Phosphoproteins/metabolism
MH  - Phosphotransferases (Alcohol Group Acceptor)/antagonists & 
      inhibitors/deficiency/genetics/metabolism
MH  - Sphingosine/*analogs & derivatives/metabolism
MH  - Transcription Factor AP-1/metabolism
MH  - Transforming Growth Factor beta/metabolism
OTO - NOTNLM
OT  - diabetes
OT  - fibrosis
OT  - nephropathy
OT  - sphingosine kinase
EDAT- 2015/09/29 06:00
MHDA- 2016/10/16 06:00
CRDT- 2015/09/29 06:00
PHST- 2015/05/20 00:00 [received]
PHST- 2015/08/31 00:00 [revised]
PHST- 2015/09/20 00:00 [accepted]
PHST- 2015/09/29 06:00 [entrez]
PHST- 2015/09/29 06:00 [pubmed]
PHST- 2016/10/16 06:00 [medline]
AID - 10.1111/1440-1681.12494 [doi]
PST - ppublish
SO  - Clin Exp Pharmacol Physiol. 2016 Jan;43(1):56-66. doi: 10.1111/1440-1681.12494.