Angiotensin II activation of the JAK/STAT pathway in mesangial cells is altered by high glucose

Farhad Amiri, Seán Shaw, Xiaodan Wang, Jie Tang, Jennifer L. Waller, Douglas C. Eaton, Mario B. Marrero

Research output: Contribution to journalArticle

110 Scopus citations

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 μmol/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. Conclusion. 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.

Original languageEnglish (US)
Pages (from-to)1605-1616
Number of pages12
JournalKidney International
Volume61
Issue number5
DOIs
Publication statusPublished - Jan 1 2002

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Keywords

  • Collagen IV
  • Diabetic nephropathy
  • Glomerular mesangial cells
  • Glycemic control
  • JAK2
  • Mesangial cells

ASJC Scopus subject areas

  • Nephrology

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