title: Costimulation with angiotensin II and interleukin 6 augments angiotensinogen expression in cultured human renal proximal tubular cells.
abstract: 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.
authors.affiliation: Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112-2699, USA.
authors.forename: Ryousuke
authors.initials: R
authors.lastname: Satou
authors.forename: Romer A
authors.initials: RA
authors.lastname: Gonzalez-Villalobos
authors.forename: Kayoko
authors.initials: K
authors.lastname: Miyata
authors.forename: Naro
authors.initials: N
authors.lastname: Ohashi
authors.forename: Akemi
authors.initials: A
authors.lastname: Katsurada
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Navar
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000808:Angiotensinogen / Q000096:biosynthesis*; D002478:Cells, Cultured; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D007093:Imidazoles; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013777:Tetrazoles; D000808:Angiotensinogen; D000804:Angiotensin II; C437965:olmesartan