High salt is positively associated with the risk of many diseases. However, little is known about the mechanisms. Here we showed that high salt increased proinflammatory molecules, while decreased anti-inflammatory and proendocytic molecules in both human and mouse macrophages. High salt also potentiated lipopolysaccharide-induced macrophage activation and suppressed interleukin 4-induced macrophage activation. High salt induced the proinflammatory aspects by activating p38/cFos and/or Erk1/2/cFos pathways, while inhibited the anti-inflammatory and proendocytic aspects by Erk1/2/signal transducer and activator of transcription 6 pathway. Consistent with the in vitro results, high-salt diet increased proinflammatory gene expression of mouse alveolar macrophages. In mouse models of acute lung injury, high-salt diet aggravated lipopolysaccharide-induced pulmonary macrophage activation and inflammation in lungs. These results identify a novel macrophage activation state, M(Na), and high salt as a potential environmental risk factor for lung inflammation through the induction of M(Na).

MR may interact with NFAT1 and activator protein-1 to control IFN-γ in T cells and to regulate target organ damage and ultimately BP. Targeting MR in T cells specifically may be an effective novel approach for hypertension treatment.

Objective-Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms. Approach and Results-Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury.MMRKO reduced intima area and intima/media ratio, Ki67-and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67-and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67-positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-κB (NF-κB) pathway was also inhibited by MMRKO, manifested by decreased p-IκB kinase-β and p-IκBα, increased IκBα expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-induciblekinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages. This manuscript was sent to Kathryn Moore, Consulting Editor, for review by expert referees, editorial decision, and final disposition. *These authors contributed equally to this article. angioplasty of coronary arteries and neointima formation after stent implantation in coronary arteries of swine. 3,4 However, the effects of MR antagonists on restenosis in human patients are uncertain. Early study has shown that spironolactone, another antagonist of MR, does not change the incidence of restenosis at 6 months after stenting in a clinical trial. Conclusions-Selective5 More recent results, however, have demonstrated that spironolactone reduces the rate of repeat revascularization at 1 year after PCI.6 Different population, length of treatments, and end points between the 2 studies may have contributed to the differential results. More fundamental studies on the cellular and molecular mechanisms how MR is involved in restenosis are needed to provide new insights for ultimately using this target to treat restenosis.Recent studies using knockout mouse models have begun to reveal the cell type-specific influence of MR in the vasculature.7 MR in monocytes/macrophages may play important roles in neointimal hyperplasia. Myeloid MR knockout (MMRKO) mouse was established and used to study the functions of macrophage MR in the cardiovascular system. The data have illustrated the importance of macrophage MR in cardiac hypertrophy, fibrosis, and inflammation. [8][9][10]...