Cyclic mechanical distension regulates renin gene transcription in As4.1 cells

The renin-producing and -secreting juxtaglomerular (JG) cells are thought to function as the baroreceptor of the kidney. The mechanism by which changes in pressure, or mechanical force, regulate renin at the molecular level has not been elucidated. The renin gene-expressing and -secreting clonal cell line As4.1 was derived from transgene-targeted oncogenesis in mice and was used as a cellular model for JG cells. As4.1 cells subjected to cyclic mechanical distension for a period of 24 h at various frequencies (0.05 or 0.5 Hz) and magnitudes (12 or 24% elongation) were analyzed via Northern analysis for renin mRNA levels. Results indicate that renin gene expression is decreased by 50-85% and returns to basal levels after a 24-h recovery period. Renin gene expression was attenuated independently of elevated cell growth or changes in renin message decay, suggesting that renin gene transcription is directly modulated by mechanical distension. Transient transfection of As4.1 cells with renin 5' flanking sequence-luciferase reporter gene constructs confirmed the role of mechanical stimulation in regulating renin gene transcription. A 43% inhibition of luciferase activity, by stretch, was observed in cells transfected with a 4,000 base pair 5' flanking sequence to the renin proximal promoter. These results demonstrate for the first time that changes in mechanical force can result in the regulation of renin gene transcription and thus provide further insight into the baroreceptor properties of renin-expressing cells.