Dynamic regulation of the angiotensinogen gene by DNA methylation, which is influenced by various stimuli experienced in daily life.

Angiotensinogen (AGT) has a central role in maintaining blood pressure and fluid balance. DNA methylation is an epigenomic modification maintaining a steady pattern in somatic cells. Herein we summarize the link between AGT regulation and DNA methylation. DNA methylation negatively regulates AGT expression and dynamically changes in response to continuous AGT promoter stimulation. High-salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT enhancer-binding protein-binding sites, thereby converting the phenotype of AGT expression from an inactive to an active state in visceral adipose tissue. Salt-dependent hypertension may be partially affected by increased adipose AGT expression. Because angiotensin II is a well-established aldosterone-releasing hormone, stimulation of adipose AGT by aldosterone creates a positive feedback loop. This effect is pathologically associated with obesity-related hypertension, although it would be physiologically favorable for humans to efficiently retain their body fluid. The clear difference in DNA demethylation patterns between aldosterone and cortisol indicates a difference in the respective target DNA-binding sites between mineralocorticoid and glucocorticoid receptors in the AGT promoter. Stimulation-induced interactions between transcription factors and target DNA-binding sites trigger DNA demethylation. Dynamic changes in DNA methylation occur in relaxed chromatin regions both where transcription factors actively interact and where transcription is initiated. In contrast to rapid histone modifications, DNA demethylation and remethylation will progress relatively slowly over days or years. A wide variety of stimuli in daily life will continue to slowly and dynamically change DNA methylation patterns throughout life. Wise choices of beneficial stimuli will improve health.

[Three cases of respiratory bronchiolitis-associated interstitial lung disease (RB-ILD): a study of HRCT-pathologic correlation].

Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) is a clinicopathologic entity occurring rarely in smokers. We report three cases of RB-ILD diagnosed pathologically by surgical lung biopsy. Cough was observed in all cases, sputum in one case and dyspnea on exertion in another. Reduction of diffusing capacity was observed in all three cases. No abnormality was found in the chest radiographs of any case. However, in high-resolution computed tomography (HRCT), ground-glass opacities and centrilobular nodules were observed in all three cases, emphysema in one case, intralobular linear or reticular opacities in two cases, small subpleural cysts in two and emphysema in one. Histologic examination of lung biopsy specimens taken by thoracoscopy showed peribronchiolar fibrosis and centrilobular intraluminal accumulation of macrophages in all three cases, centrilobular emphysema, membranous bronchioles filled with mucus and macrophages, and focal microscopic honeycombing in subpleural lesions in one case each. RB-ILD should be included in the differential diagnosis of interstitial lung disease in smokers.