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(Hypertension. 2004;43:1116.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Adjacent Expression of Renin and Angiotensinogen in the Rostral Ventrolateral Medulla Using a Dual-Reporter Transgenic Model

Julie L. Lavoie; Martin D. Cassell; Kenneth W. Gross; Curt D. Sigmund

From the Departments of Internal Medicine and Physiology and Biophysics (J.L.L., C.D.S.) and the Department of Anatomy and Cell Biology (M.D.C.), University of Iowa, Iowa City; Roswell Park Cancer Institute (K.W.G.), Buffalo, NY.

Correspondence to Dr Curt D. Sigmund, Departments of Internal Medicine and Physiology and Biophysics, 3181B Medical Education and Biomedical Research Facility (MEBRF), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242. E-mail curt-sigmund{at}uiowa.edu

	Abstract

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All components of the renin-angiotensin system are localized in the brain. However, because renin is present in very low concentrations, the mechanism by which angiotensin II is formed in the brain remains unclear. We previously reported the development of 2 transgenic mouse models using sensitive reporters, enhanced green fluorescent protein (eGFP) and ß-galactosidase (ß-Gal), to examine the cellular localization of renin and angiotensinogen in the mouse brain. To determine whether renin and angiotensinogen are coexpressed or present in neighboring cells in the rostral ventrolateral medulla (RVLM) and other cardiovascular control regions of the brain, we produced and examined double-transgenic mice, which express eGFP driven by the renin promoter (REN-1c/eGFP) and ß-gal driven by the human angiotensinogen promoter (hAGT/ß-gal). Using these reporter transgenes as sensitive markers for renin and angiotensinogen expression, we conclude that both proteins are coexpressed in the parabrachial nucleus and central nucleus of the amygdala and are in adjacent cells in the RVLM, reticular formation, bed nucleus of the stria terminalis, subfornical organ, and CA1–3 region. These data suggests that, in these areas, both renin and angiotensinogen are in close proximity providing the potential for the local formation of angiotensin I either intracellularly, when there is colocalization, or in the interstitium, when they are in juxtaposed cells.

Key Words: renin-angiotensin system • angiotensin II

	Introduction

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The effects of brain angiotensin II (Ang II) on blood pressure and fluid homeostasis are now well recognized. Although circulating Ang II can have effects on the circumventricular organs, because they are devoid of a blood-brain barrier, it has become apparent that local production of Ang II in the brain is also important. Immunoreactive Ang II has been detected in many areas of the brain that are inside the blood-brain barrier, for instance in the amygdala, parabrachial nucleus (PB), and bed nucleus of the stria terminalis (BNST).¹ In addition, it has been suggested that there is a high correlation between the distribution of Ang II and angiotensin type 1 (AT₁) receptors in the brain.² Thus, Ang II, which is released or generated in the extracellular space, could stimulate local AT₁ receptors. Notably, stimulation of AT₁ receptors present in the rostral ventrolateral medullar (RVLM) by microinjection of Ang II causes a marked increase in blood pressure, suggesting that this area might be important in the regulation of blood pressure and fluid homeostasis.³

All components of the renin-angiotensin system (RAS) have been detected in the brain. Angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) have been described to be present throughout the brain.⁴ The presence of renin, however, has been a source of substantial controversy over the years, because it is present at or below the threshold levels of detection by most assays.⁵ Consequently, clear evidence for the specific location of renin in the brain has been lacking, although renin has been reported to be present in brain homogenates and cultured cells.^6–11 Recently, a unique transgenic mouse model has been developed that uses the renin promoter to drive expression of eGFP.¹² eGFP expression in these mice mimics the pattern of expression of renin in tissues and responds to developmental and physiological cues in the kidney. Using these mice and eGFP as a sensitive reporter for renin, we identified the location of renin-expressing cells in specific areas in the brain including the RVLM and determined whether they were neurons or glia.¹³ Moreover, we previously reported the localization of angiotensinogen-expressing cells using another transgenic model in which ß-galactosidase (ß-Gal) expression was driven by the human angiotensinogen promoter (hAGT/ß-gal).¹⁴ We also reported that Ang II can be generated from overexpression of angiotensinogen and renin in the brain.^15–18 However, clear evidence demonstrating that endogenous angiotensinogen is cleaved by local endogenous renin remains lacking. To investigate whether renin and angiotensinogen are closely localized in the brain, we generated double-transgenic mice, which express both the REN-1c/eGFP and hAGT/ß-gal transgenes by crossbreeding. Using multiple coronal sections of the brain, we have assessed whether, in the RVLM and other brain areas, renin and AGT are expressed in separate cell populations in close proximity to each other or are colocalized in the same cell.

	Methods

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Animals
All experiments were performed on REN-1c/eGFP transgenic mice provided by Dr Gross’s laboratory and hAGT/ß-gal transgenic mice maintained at the University of Iowa. The mice were subsequently bred and maintained by backcross breeding to B6SJL. All transgenic mice carrying both REN-1c/eGFP and hAGT/ß-gal were generated by breeding heterozygous REN-1c/eGFP with heterozygous hAGT/ß-gal. The animals were maintained on 12-hour light/dark cycle with standard laboratory chow (LM-485; Teklab Premier Laboratory Diets, Madison, Wis) and water ad libitum. Care of the mice used in the experiments met the standards set forth by the National Institute of Health in their guidelines for the care and use of experimental animals. All procedures were approved by the University Animal Care and Use Committee at the University of Iowa. The mice were screened for the presence of the transgene by polymerase chain reaction (PCR) of tail genomic DNA as previously reported.^12,14 Age- and sex-matched nontransgenic littermates were used as controls in all experiments.

Immunohistochemistry
Mice were euthanized by CO₂ asphyxiation and then perfused transcardially with 20 mL PBS followed by 50 mL 4% paraformaldehyde in PBS. The brain was removed, postfixed at 4°C overnight, and then placed in 30% sucrose solution at 4°C. The next day, the brain was frozen and cut coronally (30 µm) using a Microm cryostat. Brain sections were permeabilized with 0.1% Triton X-100 in PBS at 25°C and incubated at 4°C for 18 hours with a rabbit antisera against LacZ conjugated with Alexa 568, which was a gift from Dr Beverly Davidson, University of Iowa. EGFP was determined as described previously.¹³ Slices were mounted on slides and visualized using a Nikon eclipse E600 fluorescence microscope equipped with a SPOT RT digital camera (Diagnostic Instruments Inc). Abbreviations for the anatomical regions of the brain are provided in Table.

View this table: [in this window] [in a new window]   Localization of GFP and ß-gal in the Brain

	Results

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A summary of the pattern of eGFP and ß-gal expression throughout the brain is shown in Table. The pattern of expression for each single transgene previously reported was confirmed in the double-transgenic mice used in this study.^13,14 To be conservative and rigorous in our interpretation of the results, we indicate with a "+?" those regions where we were unable to determine with certainty if there was colocalization or juxtaposition of the eGFP and ß-gal. This was necessary because in some cases, the presence of eGFP was ambiguous or the green fluorescence of eGFP bled through into the red fluorescence channel that was used to detect ß-gal.

In the brain stem, we found eGFP and ß-gal in adjacent cells in the RVLM (Figure 1A through 1D). In control animals, no specific ß-gal could be detected in REN-1c/eGFP or eGFP detected in hAGT/ß-gal (Figure 1E and 1F). In the amygdala, we found eGFP and ß-gal to be juxtaposed in the central nucleus (Figure 2), whereas they could only be found in adjacent cells in the BNST (Figure 3). EGFP and ß-gal was also present in adjacent cells in the reticular formation, olivary nucleus, hippocampus, pyramidal cell layer of the CA 1-3 region, the polymorphic layer of the dentate gyrus, and in the medial extension of the SFO (Table). Evidence for coexpression of eGFP and ß-gal was only observed in the PB (Figure 4), although colocalization of eGFP and ß-gal was occasionally seen in the SFO, RVLM, central nucleus of the amygdala, and the CA1-3 region (Table). Although eGFP expression was uncertain in these areas, there seemed to be presence of ß-gal in adjacent cells in the PVN and ventromedial nucleus of the hypothalamus.

View larger version (61K): [in this window] [in a new window]   Figure 1. eGFP and ß-gal expression in adjacent cells in the RVLM. Photomicrographs showing fluorescence observed in the RVLM for eGFP and a ß-gal antibody in double-transgenic mice expressing both REN-1c/eGFP and hAGT/ß-gal transgene at low (A) and high (B to D) magnification. Arrowheads indicate eGFP green fluorescence and arrows indicate ß-gal antibody red fluorescence. Expression of eGFP in a single transgenic hAGT/ß-gal mouse (E) and ß-Gal expression in a single transgenic REN-1c/eGFP mouse (F) are shown. A rough outline of the RVLM is indicated by dotted lines (A).

View larger version (64K): [in this window] [in a new window]   Figure 2. eGFP and ß-gal expression in adjacent cells in the central nucleus of the amygdala. Photomicrographs showing fluorescence observed in the central nucleus of the amygdala for eGFP in green (C and E) and a ß-gal antibody in red (B and D) in double-transgenic (A to C), REN-1c/eGFP single-transgenic (D), and hAGT/ß-gal single-transgenic (E) mouse. A, Merging of (B) and (C) to demonstrate the juxtaposition of both fluorescent signals.

View larger version (72K): [in this window] [in a new window]   Figure 3. eGFP and ß-gal expression in adjacent cells in the BNST. Photomicrographs showing fluorescence observed in the bed nucleus of the stria terminalis (BNST) for eGFP in green (C and E) and a ß-gal antibody in red (B and D) in double-transgenic (A to C), REN-1c/eGFP single-transgenic (D), and hAGT/ß-gal single-transgenic (E) mouse. A, Merging of (B) and (C) to demonstrate the juxtaposition of both fluorescent signals. Arrowheads indicate eGFP fluorescence and arrows indicate ß-gal antibody fluorescence.

View larger version (34K): [in this window] [in a new window]   Figure 4. eGFP and ß-gal colocalization in the PB. Photomicrographs showing fluorescence in the parabrachial nucleus (PB) for eGFP in green (C) and a ß-gal antibody in red (B) in a double-transgenic mouse. A, Merging of (B) and (C) to demonstrate the colocalization of both fluorescent signals.

	Discussion

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To our knowledge, this is the first study to address the presence of renin in conjunction with angiotensinogen in different regions in the brain. Using a transgenic mouse model, we were able to determine specific areas of the brain where renin and angiotensinogen are in close proximity, suggesting that Ang I might be produced in these "microdomains." Because renin is present in the brain at or below the detection level of most standard assays, we have relied on a reporter gene to determine its localization. Studies using the REN-1c/eGFP mice have shown that the transgene is expressed in the correct spectrum of tissues, and in kidney is appropriately expressed during fetal development.^12,13 Expression of the transgene in the kidney also responds to converting enzyme inhibition by recruitment of GFP expressing cells along the renal arterial tree. We are therefore confident that GFP fluorescence represents the presence and location of endogenous renin in the brain. We also previously demonstrated that expression of ß-gal in the hAGT/ß-gal mouse model accurately emulates the pattern of angiotensinogen expression.¹⁴ Consequently, combining these models provided a unique opportunity to examine the colocalization of renin and angiotensinogen expressing cells in the brain.

We found colocalization of eGFP and ß-gal in neurons of the PB, whereas they were present in adjacent glial cells and neurons in the reticular formation, olivary nucleus, RVLM, BNST, SFO, CA1-3, and central nucleus of the amygdala. Interestingly, many regions that expressed both eGFP and ß-gal have been shown to contain immunoreactive Ang II. Indeed, Ang II has been found in the SFO, area postrema, amygdala, LPB, NTS, DMNX, BNST, RVLM, and reticular formation.¹ Thus, 2 mechanisms by which Ang II may be produced need to be considered. First, expression in adjacent cells suggests that renin and AGT are secreted into the extracellular space, where they could interact to produce Ang I and subsequently Ang II. Second, the presence of renin and angiotensinogen in the same cells suggests the possibility that there may be intracellular formation of Ang I with subsequent production of Ang II, either intracellularly or in the interstitium. Indeed, ACE has been found to be present ubiquitously throughout the brain and thus should not be a limiting factor toward the production of Ang II.¹⁹ That Ang II has been found in nerve terminals supports this notion.¹ An intra-cellular pathway for the RAS, although controversial, has been suggested.²⁰ This has been of particular interest recently because it has been reported that an alternative transcript of renin that encodes a nonsecreted protein devoid of a signal peptide and having only two-thirds of the prosegment exists in the brain.^21–23 Thus, this would form an active renin protein that would remain intracellular and could potentially interact with intracellular angiotensinogen.

In addition, all of the areas mentioned contain a high density of AT₁ receptors; stimulation of the AT₁ receptors by microinjection of Ang II directly into many of those areas causes a significant increase in blood pressure.^2,4 Therefore, it is possible that the RAS is present as a local paracrine system in many of these areas where both the generation and local action of Ang II can occur. It is now well established that blockade of AT₁ receptors by inhibitors or antisense, specifically in the brain, produces a significant decrease in blood pressure in models of hypertension, thus implicating the local action of Ang II in the hypertensive state.^24–27 With the identification of renin and angiotensinogen co-expressing and adjacent cells in the brain, direct experimental support for the generation of Ang II from angiotensinogen and renin expressed or released from these cells needs to be obtained. Because of the low levels of renin present in these cells, this will remain a difficult task.

	Acknowledgments

 
We thank Deborah R. Davis for assistance with the mice used in this study.

This work was supported by National Institutes of Health grants HL48058, HL61446, HL55006 (to C.D.S.), and HL48459 (to K.W.G.). We also acknowledge NCI Cancer Center Support grant CA16056 awarded to Roswell Park Cancer Institute. Dr Lavoie is the recipient of an American Heart Association Heartland Affiliate Postdoctoral Fellowship. We gratefully acknowledge the generous research support of the Roy J. Carver Trust.

Received January 22, 2004; first decision February 10, 2004; accepted February 23, 2004.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 43/5/1116    most recent 01.HYP.0000125143.73301.94v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lavoie, J. L. Articles by Sigmund, C. D. Search for Related Content PubMed PubMed Citation Articles by Lavoie, J. L. Articles by Sigmund, C. D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Autonomic, reflex, and neurohumoral control of circulation Animal models of human disease Gene expression Genetically altered mice