Despite overwhelming evidence for the role of the renin-angiotensin system (RAS) in blood pressure control, there is considerable disagreement over its involvement in hypertension. In part, this relates to the lack of a transgenic model which replicates endogenous renin gene expression and normal physiological regulation of the RAS. The general goal of the proposed studies is to investigate the mechanisms that direct appropriate cell-specific expression of the renin gene. In particular, the applicant wishes to determine the role of flanking and intervening sequences in the renin gene that contribute to appropriate cell- and tissue-specific expression of renin and prorenin. Because cell culture models of renal renin gene expression may not utilize physiologically relevant mechanisms to express the renin gene, the experiments proposed in this application make use of transgenic mice. Constructs will be generated to test the role of flanking and intervening sequences both in directing renin gene expression to appropriate physiological sites, and in preventing renin expression at inappropriate sites. The applicant will then use information generated in these studies to target a supervital marker, green fluorescent protein (GFP), to the renal juxtaglomerular (JG) cells. This will permit him to identify JG cells directly, in vivo, by fluorescence microscopy and to isolate these cells using flow cytometry sorting. It is hoped that these cells will prove useful as a model to study renin gene expression, prorenin processing and renin secretion in vitro. Understanding the mechanisms that regulate normal renin synthesis and secretion should help to identify pathophysiological changes in hypertensive patients that result in inappropriately high renin secretion, and thus provide new therapeutic targets for the treatment of hypertension.
| Catanzaro, D F; Chen, R; Yan, Y et al. (1999) Appropriate regulation of renin and blood pressure in 45-kb human renin/human angiotensinogen transgenic mice. Hypertension 33:318-22 |
| Yan, Y; Chen, R; Pitarresi, T et al. (1998) Kidney is the only source of human plasma renin in 45-kb human renin transgenic mice. Circ Res 83:1279-88 |
| Yan, Y; Hu, L; Chen, R et al. (1998) Appropriate regulation of human renin gene expression and secretion in 45-kb human renin transgenic mice. Hypertension 32:205-14 |
| Yan, Y; Jones, C A; Sigmund, C D et al. (1997) Conserved enhancer elements in human and mouse renin genes have different transcriptional effects in As4.1 cells. Circ Res 81:558-66 |
