title: Angiotensin II activation of the JAK/STAT pathway in mesangial cells is altered by high glucose.
abstract: BACKGROUND
  Both high glucose (HG) and angiotensin II (Ang II) causes glomerular mesangial cell (GMC) growth and increased synthesis of matrix proteins like collagen IV contributing to diabetic nephropathy. We have recently found that exposure of vascular smooth muscle cells to HG augments the Ang II activation of the growth promoting JAK/STAT pathway. We hypothesized that Ang II activation of the JAK/STAT pathway is altered by HG in GMC, and that this pathway might be linked to the Ang II-induced growth and overproduction of collagen IV in GMC in HG conditions.
  
  
  METHODS
  GMC were cultured under normal glucose (NG; 5.5 mmol/L) and HG (25 mmol/L) for 48 hours and stimulated with Ang II (0.1 micromol/L) for various times. GMC lysate was then immunoprecipitated and/or immunoblotted with SHP-1, SHP-2 and phosphospecific JAK2 and STAT antibodies. The HG and Ang II induced growth and collagen IV synthesis studies were performed in GMC transfected with JAK2 antisense or JAK2 sense. GMC growth was monitored via [3H]-thymidine incorporation, and collagen IV synthesis via ELISA.
  
  
  RESULTS
  We found that Ang II-induced JAK2, STAT1, STAT3, STAT5A/B and SHP-2 phosphorylations were enhanced by HG, whereas that of SHP-1 was reduced. Ang II-induced growth and collagen IV synthesis also were increased under HG conditions. Transfection of GMC with JAK2 antisense oligonucleotides blocked the Ang II-induced growth and collagen IV synthesis in both NG and HG conditions.
  
  
  CONCLUSIONS
  These results provide evidence that activation of the JAK/STAT pathway by HG or/and Ang II may be of importance in the increased GMC cell growth and collagen IV synthesis that is seen in diabetic nephropathy.
authors.affiliation: Vascular Biology Center, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912-2500, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Amiri
authors.forename: Seán
authors.initials: S
authors.lastname: Shaw
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Waller
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Eaton
authors.forename: Mario B
authors.initials: MB
authors.lastname: Marrero
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D005947:Glucose / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008297:Male; D008894:Milk Proteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D024141:Collagen Type IV; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; C494094:Stat5a protein, rat; D015534:Trans-Activators; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; C509250:Ptpn6 protein, rat; D005947:Glucose