Interferon-γ biphasically regulates angiotensinogen expression via a JAK-STAT pathway and suppressor of cytokine signaling 1 (SOCS1) in renal proximal tubular cells

Renal inflammation modulates angiotensinogen (AGT) production in renal proximal tubular cells (RPTCs) via inflammatory cytokines, including interleukin-6, tumor necrosis factor alpha, and interferon-gamma (IFN-gamma). Among these, the effects of IFN-gamma on AGT regulation in RPTCs are incompletely delineated. This study aimed to elucidate mechanisms by which IFN-gamma regulates AGT expression in RPTCs. RPTCs were incubated with or without IFN-gamma up to 48 h. AGT expression, STAT1 and STAT3 activities, and SOCS1 expression were evaluated. RNA interference studies against STAT1, SOCS1, and STAT3 were performed to elucidate a signaling cascade. IFN-gamma decreased AGT expression at 6 h (0.61 +/- 0.05, ratio to control) and 12 h (0.47 +/- 0.03). In contrast, longer exposure for 24 and 48 h increased AGT expression (1.76 +/- 0.18, EC50 +/- 3.4 ng/ml, and 1.45 +/- 0.08, respectively). IFN-gamma treatment for 6 h strongly induced STAT1 phosphorylation and SOCS1 augmentation, and decreased STAT3 activity. However, STAT1 phosphorylation and SOCS1 augmentation waned at 24 h, while STAT3 activity increased. RNA interference studies revealed that activation of STAT1-SOCS1 axis decreased STAT3 activity. Thus, IFN-gamma biphasically regulates AGT expression in RPTCs via STAT3 activity modulated by STAT1-SOCS1 axis, suggesting the STAT1-SOCS1 axis is important in IFN-gamma-induced activation of the intrarenal renin-angiotensin system.-Satou, R., Miyata, K., Gonzalez-Villalobos, R. A., Ingelfinger, J. R., Navar, L. G., Kobori, H. Interferon-gamma biphasically regulates angiotensinogen expression via a JAK-STAT pathway and suppressor of cytokine signaling 1 (SOCS1) in renal proximal tubular cells. FASEB J. 26, 1821-1830 (2012). www.fasebj.org