Abstract-The brain renin-angiotensin system is implicated in the regulation of blood pressure (BP) and fluid homeostasis.Recent studies reveal that 2 forms of renin are expressed in the brain of rodents and humans: secreted prorenin and a nonsecreted intracellular form of active renin (icREN). Although the intracellular action of renin has long been postulated, no data supporting its role in BP regulation has been reported. Therefore, we directly evaluated whether this form of renin has physiological implications for BP regulation by characterizing transgenic mice expressing human icREN driven by the glial fibrillary acidic protein (GFAP) promoter and comparing it with similar mice expressing the secreted form of renin. GFAP-icREN mice express hREN primarily in the brain and at the same level of expression as GFAP-secreted prorenin. Unlike the secreted form, which can be detected in cerebrospinal fluid, no human renin could be detected in the cerebrospinal fluid of GFAP-icREN mice. GFAP-icREN mice were then bred with transgenic mice expressing human angiotensinogen, also driven by the GFAP promoter. Double-transgenic mice expressing either the intracellular renin (2.0Ϯ0.12 mL/10 g/day) or secreted renin (2.8Ϯ0.3 mL/10 g/day) exhibited an increase in drinking volume compared with nontransgenic littermates (1.5Ϯ0.1 mL/10 g/day). Both models exhibited an increase in mean arterial pressure (137Ϯ5 and 133Ϯ8 mm Hg, respectively) compared with control littermates (115Ϯ3 mm Hg), which could be rapidly reduced after ICV injection of losartan. These data support the concept of an intracellular form of renin in the brain, which may provoke functional changes in fluid homeostasis and BP regulation. Key Words: renin-angiotensin system Ⅲ brain T he renin-angiotensin system (RAS) is well known for its effects on blood pressure (BP) and fluid homeostasis. Although these actions were long thought to be caused primarily by the circulating RAS, in the past decade, it has become apparent that local RAS have an important physiological role. For instance, all components of the RAS are present in the heart, kidney, adrenal gland, and brain (reviewed in Reference 1). It is now becoming clear that cells expressing renin and angiotensinogen (AGT) are in close proximity to each other and to cells expressing angiotensin type 1 (AT 1 ) receptors in a number of tissues including the brain. 2,3 This suggests the potential for local synthesis and action of angiotensin independent of its production in the systemic circulation. In addition, some cells in the brain coexpress both proteins. 3 This has led us and others to question whether the RAS can function intracellularly either through the intracellular production or intracellular action of angiotensin II (Ang II). Interestingly, the intracellular action of Ang II was proposed as early as 1971 when Robertson and Khairallah 4 reported nuclear localization of the peptide in smooth and cardiac muscle. More recently, Re 5 and others 6 have described Ang II as part of a class of peptide hormones th...

Hypertension is a polygenic and multi-factorial disorder that is extremely prevalent in western societies, and thus has received a great deal of attention by the research community. The renin-angiotensin system has a strong impact on the control of blood pressure both in the short- and long-term, making it one of the most extensively studied physiological systems. Nevertheless, despite decades of research, the specific mechanisms implicated in its action on blood pressure and electrolyte balance, as well as its integration with other cardiovascular pathways remains incomplete. The production of transgenic models either over-expressing or knocking-out specific components of the renin-angiotensin system has given us a better understanding of its role in the pathogenesis of hypertension. Moreover, our attention has recently been refocused on local tissue renin-angiotensin systems and their physiological effect on blood pressure and end-organ damage. Herein, we will review studies using genetic manipulation of animals to determine the role of the endocrine and tissue renin-angiotensin system in hypertension. We will also discuss some untraditional approaches to target the renin-angiotensin system in the kidney.

Soluble epoxide hydrolase (sEH) is the major enzyme responsible for the metabolism and inactivation of epoxyeicosatrienoic acids (EETs). EETs are produced by the cytochrome P450 (CYP) epoxygenase pathway of arachidonic acid (AA) metabolism and tend to be anti-hypertensive, anti-inflammatory and protective against ischemic injury. Since the metabolism of EETs by sEH reduces or eliminates their bioactivity, inhibition of sEH has become a therapeutic strategy for hypertension and inflammation. sEH is found in nearly all tissues so the systemic application of inhibitors is likely to affect more than blood pressure and inflammation. In the central nervous system, EETs are thought to play a role in the regulation of local blood flow, protection from ischemic injury, inhibition of inflammation, the release of peptide hormones and modulation of fever. However, little is known about region- and cell-specific expression of sEH in the brain. In the mouse brain, expression of sEH was found widely in cortical and hippocampal astrocytes and also in a few specific neuron-types in the cortex, cerebellum, and medulla. To assess the functional significance of neuronal sEH, we generated a transgenic mouse model, which over-expresses sEH specifically in neurons. Transgenic mice showed increased neuron labeling in cortex and hippocampus with little change in labeling of other brain regions. Despite a 3-fold increase in sEH activity in the brain, there was no change in arterial pressure. This data provides new information required for studying the central roles of the cytochrome P450 epoxygenase pathway.

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With the completion of the human genome project and the sequencing of many genomes of experimental models, there is a pressing need to determine the physiological relevance of newly identified genes. Gene-targeting approaches have become an important tool in our arsenal to dissect the significance of genes expressed in many tissues. A wealth of experimental models has been made to assess the role of gene expression in renal function and development. The development of new and informative models is presently limited by the anatomic complexity of the kidney and the lack of cell-specific promoters to target the numerous diverse cell types in that organ. Because of this, new approaches may have to be developed. In this review, we will discuss several untraditional methods to target gene expression to the kidney. These approaches should provide some additional tricks and tools to help in developing additional informative models for studying renal physiology.

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