title: Macrophage-derived IL-6 contributes to ANG II-mediated angiotensinogen stimulation in renal proximal tubular cells.
abstract: 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.
authors.affiliation: Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Ryan
authors.initials: R
authors.lastname: O'Leary
authors.affiliation: Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Harrison
authors.initials: H
authors.lastname: Penrose
authors.affiliation: Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana rsato@tulane.edu.
authors.forename: Ryousuke
authors.identifier: 0000-0001-6505-9722
authors.initials: R
authors.lastname: Satou
mesh_terms: D000808:Angiotensinogen / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D053583:Interleukin-1beta; D015850:Interleukin-6; D044140:Receptor, Angiotensin, Type 1; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014409:Tumor Necrosis Factor-alpha; D000808:Angiotensinogen; D053612:Janus Kinases
keywords: angiotensin II; angiotensinogen; interleukin-6; macrophage; renin-angiotensin system