Costimulation with angiotensin II and interleukin 6 augments angiotensinogen expression in cultured human renal proximal tubular cells

Am J Physiol Renal Physiol. 2008 Jul;295(1):F283-9. doi: 10.1152/ajprenal.00047.2008. Epub 2008 May 7.


Augmented intrarenal ANG II stimulates IL-6, which contributes to renal injury. The expression of intrarenal angiotensinogen (AGT) is enhanced by increased intrarenal ANG II in human renin/human AGT double transgenic mice. ANG II also augments AGT expression in hepatocytes and cardiac myocytes. However, the mechanisms underlying AGT augmentation by ANG II and the contribution of IL-6 to this system are poorly understood. This study was performed in human renal proximal tubular epithelial cells (HRPTECs) to test the hypothesis that IL-6 contributes to the upregulation of AGT expression by ANG II. Human kidney-2 (HK-2) cells, immortalized HRPTECs, were incubated with 10(-7) M ANG II and/or 10 ng/ml IL-6 for up to 24 h. AGT mRNA and protein expressions were measured by real-time RT-PCR and ELISA, respectively. The activities of NF-kappaB and STAT3 were evaluated by Western blotting and EMSA. Stimulation with either ANG II or IL-6 did not significantly alter AGT mRNA or protein expression. In contrast, costimulation with ANG II and IL-6 significantly increased AGT mRNA and protein expressions (1.26 +/- 0.10 and 1.16 +/- 0.13 over control, respectively). Olmesartan, an ANG II type 1 receptor blocker, and an IL-6 receptor antibody individually inhibited this synergistic effect. NF-kappaB was also activated by costimulation with ANG II and IL-6. Phosphorylation and activity of STAT3 were increased by stimulation with IL-6 alone and by costimulation. The present study indicates that IL-6 plays an important role in ANG II-mediated augmentation of AGT expression in human renal proximal tubular cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Angiotensinogen / biosynthesis*
  • Cells, Cultured
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-6 / pharmacology*
  • Kidney Tubules, Proximal / cytology*
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / physiology*
  • NF-kappa B / physiology
  • RNA, Messenger / metabolism
  • STAT3 Transcription Factor / physiology
  • Tetrazoles / pharmacology
  • Up-Regulation


  • Imidazoles
  • Interleukin-6
  • NF-kappa B
  • RNA, Messenger
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tetrazoles
  • Angiotensinogen
  • Angiotensin II
  • olmesartan