The development of angiotensin II (Ang II)-dependent hypertension involves increased infiltration of macrophages (MΦ) and T-cells into the kidney and consequent elevation of intrarenal cytokines including interleukin 6 (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, this study investigated whether Ang II-treated MΦ induce AGT upregulation in renal proximal tubular cells (PTC). MΦ were treated with 0-10-6 M Ang II for up to 48 hr. PTC 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, 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 signal transducers and activators of transcription 3 (STAT3) were observed in PTC receiving culture medium from Ang II-treated MΦ. Addition of a neutralizing IL-6 antibody to the collected medium attenuated phosphorylation of STAT3 and AGT augmentation in PTC. Furthermore, a Janus kinase 2 (JAK2) inhibitor also suppressed STAT3 phosphorylation and AGT augmentation in PTC. These results demonstrate that Ang II-induced IL-6 elevation in MΦ enhances activation of the JAK-STAT pathway and consequent AGT upregulation in PTC, suggesting involvement of an immune response in driving intrarenal RAS activity.
- angiotensin II
- Copyright © 2015, American Journal of Physiology - Renal Physiology