Renin gene expression
Juxtaglomerular (JG) cells are located in renal afferent arterioles close to the glomerulus. Here they are able to sense fluctuations in systolic pressure, ion composition in tubular fluid detected by the adjacent macula densa cells, sympathetic influences and hormonal influences, and respond by secreting renin. During development, renin expression in the primitive vessels of the fetal kidney gradually shrinks from the entire length of the afferent arteriole, to a more restricted length in the neonate and in the adult becomes confined just to the JG cells proximal to the glomerulus. 1 This reflects the important role of renin in kidney development, where targeted renin gene deletion or pharmacological blockade of the renin–angiotensin system results in renal pathology and abnormal morphology. 2,3 Under stimulatory conditions such as renal artery stenosis, hydronephrosis, low salt diet or blockade of angiotensin II formation, reactivation of renin expression occurs in a subset of medial cells of the larger renal arteries. 4–6 In the adrenal, renin is maximal at day 15 postcoitus and later retracts to the zona glomerulosa. 7 Furthermore, low salt plus enalapril switches on renin mRNA in rat heart.
The mechanism by which renin expressing cells retract along the afferent arterioles during development or can be recruited back to express renin in adult animals is not known. It is, however, well known that enhancers play a pivotal role in both tissue-specific gene expression and in controlling the activation of gene expression in response to physiological cues. Two models have been proposed – a rate model and a probability (or on/off switching) model (Fig. 1). The latter refers to the possibility that gene expression in cell populations occurs in a mosaic, or ‘variegated’ manner such that the gene is switched fully on in some cells and switched fully off in others. 9–12 The enhancer elements work by suppressing the silencing mechanisms. Stimuli thus increase the proportion of cells that express the gene. However, although some support has come from studies of globin genes, this model remains untested in the context of a gene that is subject to continuous fluctuations in physiological regulation.
The renin promoter is weak, 13 but transcription can be activated in vitro by a far upstream enhancer. 14–17 The present study therefore asked whether this enhancer directs renin expression by the on-off switching model. The mouse enhancer, located 2.5 kb upstream of the transcription start site of the mouse Ren-1c gene, was tested in a system in which expression could be detected in individual cells, something that has not previously been attempted for renin.
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