Nakagawa and Sigmund Regulation of the Brain RAS 11 processing proteases including tonin and cathepsin G with a broad spectrum of substrate affinities. 27 Ang-(1–12), a peptide fragment of AGT has also been reported to be expressed in the brain; and chymase or ACE can generate Ang-II from Ang-(1–12). 28, 29 It was argued that Ang-(1–12) may be a bona fide precursor to Ang-II evidencing a nonrenin Ang-II generation pathway because immunoneutralization of Ang-(1–12) reduces BP in (mRen2) 27 rats. 30 However, does the antisera have the selectivity to specifically target Ang-(1–12) and not full-length AGT? Thus, whereas the evidence favors a renin-dependent model of Ang-II generation, and although there is no direct evidence supporting renin-independent Ang-II generation, we cannot formally rule out the possibility that cathepsin G or an Ang-(1–12)–hydrolyzing enzymes is involved in the nonrenin-dependent generation of Ang-II in the brain. Indeed, if these enzymes, like renin, act species specifically, it could explain why mice expressing vast quantities of human AGT are not hypertensive. It is interesting to note that human cathepsin G has a broadened specificity than the mouse isoform and Ang-(1–12) processing mechanisms differ between species. 31, 32

There is more known about the mechanisms governing expression of the renin gene than any other RAS gene. The isolation of the As4. 1 cell line, a renin-expressing cell line derived from renin-expressing kidney tumor, became a turning point leading us and others to identify critical DNA sequences in the proximal promoter and distal enhancer that were necessary for the maintenance of high-level renin expression (Figure 1). 33–36 Deletion of the human or mouse renin distal enhancer preserves tissue specificity in mice but results in a decrease in the overall level of renin expression in kidney. 37, 38 Interestingly, deletion of the distal enhancer also blunts the renin protein response to physiological cues in several tissues including the brain. 39 Whether there are specific sequences in the renin enhancer or promoter that direct