Macrophage-derived IL-6 contributes to ANG II-mediated angiotensinogen stimulation in renal proximal tubular cells

Am J Physiol Renal Physiol. 2016 May 15;310(10):F1000-7. doi: 10.1152/ajprenal.00482.2015. Epub 2016 Mar 23.


The development of ANG II-dependent hypertension involves increased infiltration of macrophages (MΦ) and T cells into the kidney and the consequent elevation of intrarenal cytokines including IL-6, which facilitates the progression of hypertension and associated kidney injury. Intrarenal renin-angiotensin system (RAS) activation, including proximal tubular angiotensinogen (AGT) stimulation, has also been regarded as a cardinal mechanism contributing to these diseases. However, the interaction between immune cells and intrarenal RAS activation has not been fully delineated. Therefore, the present study investigated whether ANG II-treated MΦ induce AGT upregulation in renal proximal tubular cells (PTCs). MΦ were treated with 0-10(-6) M ANG II for up to 48 h. PTCs were incubated with the collected medium from MΦ. In ANG II-treated MΦ, IL-6 mRNA and protein levels were increased (1.86 ± 0.14, protein level, ratio to control); moreover, IL-6 levels were higher than TNF-α and IL-1β in culture medium isolated from ANG II-treated MΦ. Elevated AGT expression (1.69 ± 0.04, ratio to control) accompanied by phosphorylated STAT3 were observed in PTCs that received culture medium from ANG II-treated MΦ. The addition of a neutralizing IL-6 antibody to the collected medium attenuated phosphorylation of STAT3 and AGT augmentation in PTCs. Furthermore, a JAK2 inhibitor also suppressed STAT3 phosphorylation and AGT augmentation in PTCs. These results demonstrate that ANG II-induced IL-6 elevation in MΦ enhances activation of the JAK-STAT pathway and consequent AGT upregulation in PTCs, suggesting involvement of an immune response in driving intrarenal RAS activity.

Keywords: angiotensin II; angiotensinogen; interleukin-6; macrophage; renin-angiotensin system.

Publication types

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

MeSH terms

  • Angiotensinogen / metabolism*
  • Animals
  • Cells, Cultured
  • Culture Media, Conditioned
  • Hypertension / etiology*
  • Hypertension / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism*
  • Janus Kinases / metabolism
  • Kidney Tubules, Proximal / immunology*
  • Kidney Tubules, Proximal / metabolism
  • Macrophages / metabolism*
  • Male
  • Rats
  • Receptor, Angiotensin, Type 1 / metabolism
  • STAT3 Transcription Factor / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • Culture Media, Conditioned
  • Interleukin-1beta
  • Interleukin-6
  • Receptor, Angiotensin, Type 1
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Tumor Necrosis Factor-alpha
  • Angiotensinogen
  • Janus Kinases