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(Hypertension. 2004;43:324.)
© 2004 American Heart Association, Inc.

Scientific Contribution

Decrease in Hypothalamic Gamma Adducin in Rat Models of Hypertension

From Departments of Physiology and Functional Genomics and Pharmacodynamics, Colleges of Medicine and Pharmacy and the University of Florida McKnight Brain Institute, Gainesville.

Correspondence to Dr Mohan K. Raizada, Department of Physiology and Functional Genomics, University of Florida, College of Florida, Box 100274, Gainesville, FL 32610. E-mail mraizada{at}phys.med.ufl.edu

	Abstract

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We have previously shown that a decrease in hypothalamic gamma adducin (-adducin) is associated with hypertension in the spontaneously hypertensive rat (SHR). In view of many inherent issues with SHR, our objective in the present study was to provide proof of this concept with the use of 2 nongenetic rat models of hypertension. Subcutaneous angiotensin II (Ang II) infusion for 2 weeks (55 ng/kg per day) resulted in an increase in blood pressure (BP) of 18 mm Hg. This was associated with a 70% decrease in hypothalamic -adducin. Concomitant administration of losartan attenuated the development of hypertension and a decrease in -adducin. Deoxycorticosterone acetate salt-induced hypertension also caused a 70% decrease in hypothalamic -adducin. Finally, neuronal cultures from neonatal rat brains were incubated with 100 nmol/L Ang II for 4 hours to mimic the in vivo Ang II infusion rat model. This chronic incubation with Ang II resulted in a 60% decrease in the neuronal -adducin. Taken together, these observations strengthen our hypothesis that a decrease in hypothalamic -adducin is linked to hypertension.

Key Words: angiotensin • hypertension • brain • hypothalamus

	Introduction

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The central nervous system (CNS) plays a critical role in the control of many cardiovascular functions by regulating such physiological mechanisms as sympathetic nerve activity, vasopressin release, and baroreceptor reflexes.^1,2 Dysregulation of one or more of these physiological pathways is associated with the development and maintenance of hypertension.^2–4 For example, an increased sympathetic nerve activity that is linked to animal models and human hypertension has been identified as one of the key physiological mechanisms that is altered in neurogenic hypertension.² Despite abundant evidence supporting dysregulated CNS function, the therapeutic potential of these findings in the control and treatment of neurogenic hypertension has not been fully explored. In part, this may be because of the fact that little is known about the cellular and molecular basis of this alteration in hypertension.

Our research group has been involved in filling this important gap in knowledge by identifying and characterizing genes and signaling pathways that are uniquely altered in the brain of the spontaneously hypertensive rat (SHR).^2,5 These studies have demonstrated that the expression of gamma-adducin (-adducin), a cytosolic protein, is reduced in the hypothalamic-brainstem areas of the SHR.⁶ -Adducin belongs to a family of cytosolic proteins whose dimerization with an isoform plays a critical role in the control of cytoskeletal-mediated cellular processes.⁷ For example, / heterodimers of adducin have been demonstrated to regulate protein kinases involved in vesicular trafficking, calcium mobilization, and transmitter release.⁷ In addition, its interaction with Na⁺/K⁺ ATPase regulates the pump activity and thus regulates neuronal activity.^8,9 These observations, together with our data on -adducin expression, lead us to propose that a decrease in the expression of this protein is one of the key early molecular events that could be linked to the development and maintenance of neurogenic hypertension.⁶ This hypothesis is consistent with association studies indicating a linkage in , ß, and adducin polymorphisms with hypertension.^10–12 Thus, our objective in the present study was to validate our hypothesis that a decrease in brain -adducin is linked to hypertension by using two nongenetic rat models of hypertension that are known to have a neurogenic component. This is critical in recognizing the therapeutic potential of this linkage in view of many inherent issues related to the genetic background of the SHR and its normotensive control.^13,14 Our studies demonstrate that hypertension-induced by either Ang II infusion or deoxycorticosterone acetate (DOCA)/salt treatment in normotensive rats is linked to a decrease in the levels of hypothalamic -adducin.

	Methods

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Animals
Twelve-week-old male Sprague-Dawley (SD) rats were used for all in vivo studies. They were obtained from Charles River Laboratories (Wilminton, Mass). Animals were housed and maintained at 25±2°C on a 12:12-hour light–dark cycle, and normal rat chow (Harlan, Teklad) and water were provided ad libitum.

Subcutaneous Ang II infusion was performed for 2 weeks to induce hypertension in male SD rats. Twelve SD rats were fitted with ALZET 2004 minipumps (Durect Corp, Cupertino, Calif) as described previously.¹⁵ Minipumps were filled with either physiological saline (n=6) or Ang II (n=6) in such a way that pumps delivered 0.25 µL/h for 2 weeks for a final dose of Ang II of 55 ng/kg per day. In a subgroup of rats, losartan was administered in the drinking water during Ang II infusion. This dose of losartan was effective in normalizing Ang II-induced blood pressure (BP).¹⁶

Hypertension was also induced in the SD rats by administration of DOCA (Sigma, St Louis, Mo) compounded into 25 mg pellets. Animals (n=6) were anesthetized with a rodent cocktail containing ketamine (1.5 mL of a 100 mg/mL solution), xylazine (1.5 mL of 20 mg/mL solution), and acepromazine (0.5 mL of 10 mg/mL solution). This rodent cocktail was injected intramuscularly at a dose of 0.5 to 0.7 mL/kg. One DOCA pellet was inserted subcutaneously between the shoulder blades, during which time the left kidney was also removed as described.^17,18 After recovery, rats were maintained on a 1% saline drinking water in place of tap water ad libitum. A control group of SD rats (n=6) underwent a sham surgical protocol, and cellulose was implanted instead of a DOCA pellet in parallel with the experimental group. Animals were studied 4 weeks after surgery. Indirect blood pressure was measured by the tail-cuff method as described previously.¹⁵ The University Animal Care and Use Committee approved all animal protocols.

Neuronal Cultures
Neuronal cultures were prepared from the Wistar Kyoto strain of normotensive rat brains exactly as described previously.¹⁹ Dissociated brain cells (3 x 10⁷ cell/35-mm-diameter dish) were plated onto poly L-lysine precoated culture dishes in Dulbecco modified eagles medium containing 10% horse serum and enriched for neuronal cells as described previously.¹⁹ Ten-day-old culture, which contained 90% neurons and 10% glial cells, was used for all the experiments.¹⁹

Western Blotting for -Adducin
Hypothalamic and brainstem tissue blocks or neuronal cultures were homogenized in the lysis buffer (50 mmol/L Tris, pH7.4, 150mmol/L NaCl, 10% glycerol, 0.1% SDS, 0.5% sodium deoxycholate, 1% Triton x-100, 2 mmol/L EDTA, 1 mmol/L pherylmethylsulfonyl fluoride, 10 µg/mL aprotinin, and 2 µg/mL leupeptin). The lysates were centrifuged at 5000g and 20 µg of proteins from the supernatants were separated by SDS-PAGE.²⁰ Proteins were transferred to a nitrocellulose membrane and used for Western blotting with the use of -adducin–specific antibody as follows: membranes were incubated with anti-rabbit -adducin polyclonal antibody (1:1000 dilution in PBS) and -adducin bands were developed essentially as described previously.⁶ -Adducin protein bands were quantitated by normalizing to endogenous alpha tubulin protein.⁶

Characterization and specificity of -adducin antibody has been previously established.²¹ The antibody showed no cross-reactivity to - or ß-adducins.^21,22 It recognizes two protein bands of 120 kDa and 105 kDa, which is consistent with our previous data⁶ and those of others.^21,22 Both 120-kDa and 105-kDa bands were used to represent total -adducin levels for normalization with tubulin. In preliminary experiments, we had determined that there was a linear relationship between total proteins loaded on the gel (5 to 50 µg protein) with the amount of -adducin and tubulin immunoreactivity. Thus, all our subsequent experiments were performed with 20 µg lysate proteins.

Experimental Groups and Statistical Analysis
Six animals per group and 5 culture dishes per data point were used. Neurons from each culture dish originated by pooling cells from 2 to 4 animals. Images from autoradiographs were captured with GS700 densitometer (Bio-Rad Laboratories). The immunoreactivity bands were quantitated using Quantity One Analysis software (Bio-Rad Laboratories) and corrected for equal sample loading by normalizing with standard protein. Data are presented as mean±SE. Comparison between control and experimental groups were made using the Student t test with statistical software.

	Results

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-Adducin in the Brains of Hypertensive Rats
Two nongenetic rat models of hypertension have been used to compare the levels of -adducin and to provide proof of the concept that a decrease in this cytosolic protein is linked to hypertension.

Ang II infusion for 2 weeks in SD rats resulted in the development of hypertension. Mean BP was 128±2 mm Hg (n=6) in Ang II-infused rats, whereas it was 110±4 mm Hg (n=6) in saline-infused rats (Figure 1 A). We have previously reported a 60% increase in the heart weight-to-body weight ratio after a similar 2-week Ang II infusion.¹⁵ Establishment of this hypertensive state in the current study was associated with a 70% decrease in hypothalamic -adducin levels (Figure 1B and C). Administration of losartan attenuated the development of high BP.¹⁶ This attenuation prevented a decrease in hypothalamic -adducin levels (Figure 1C). In contrast to the hypothalamus, levels of -adducin in the brainstem of Ang II-induced hypertensive rats did not decrease and thus were not different from control rats (Figure 1D and E).

View larger version (12K): [in this window] [in a new window]   Figure 1. Effect of chronic Ang II infusion on -adducin expression in the brain. A, Effect on BP. Osmotic minipumps were implanted to deliver saline (control, C) or 55 ng/kg per minute Ang II for 2 weeks. Indirect BP was measured by the tail-cuff method.15 Data are mean±SE; n=6 per group; *P<0.05. B, Western blot analysis of hypothalamic -adducin. Hypothalamic areas from the control (C), Ang II-infused (Ang II), and Ang II + losartan (Ang II + Los) rats were homogenized in lysis buffer, and 20 µg proteins were subjected to Western blot analysis with -adducin antibody. Both 120 kDa and 105 kDa protein bands representing -adducin were quantitated as described in the methods. Data are representative of 3 experiments in which hypothalamic areas of 2 rats from each group were pooled. C, Quantitation of hypothalamic -adducin. Data from 3 blots were normalized with tubulin and presented as percent of control in which levels in untreated control rats was set as 100%. *Significant difference between Ang II group compared with the other two groups (P<0.05). D and E, -Adducin levels in the brainstem of Ang II-infused rat. Brainstem from 3 control (C) and 3 Ang II-infused (Ang II) rats from the same group as described in A and B were subjected to Western blotting (D). Data from 3 blots were normalized with tubulin (E).

Next, we used a DOCA-salt rat model of hypertension. This treatment resulted in an increase in BP of 43 mm Hg (116±4mm Hg in control rats versus 159±8 mm Hg in DOCA-salt rats; n=6) (Figure 2 A). The DOCA-salt–induced hypertension was associated with a 70% decrease in -adducin in the hypothalamus (Figure 2B and C). In contrast, brainstem -adducin levels did not change between the two groups (Figure 2D).

View larger version (11K): [in this window] [in a new window]   Figure 2. Effect of DOCA-salt–induced hypertension on hypothalamic -adducin. A, Effect of BP. Six control (C) and 6 DOCA-salt (DOCA) rats were prepared essentially as described in Methods. Indirect BP were measured 4 weeks after treatment. Data are mean±SE; n=6; *P<0.05. B and C, Western blotting of hypothalamic -adducin. Hypothalamic areas from control (C) and DOCA-salt (DOCA) rats were dissected and subjected to Western blotting as described in Methods. B, Representative autoradiogram. C, Quantitation of -adducin bands. *Significantly different from control (P<0.01; n=3). D, Levels of -adducin in the brainstem of DOCA-salt rats. Brainstems from each group of rats were dissected and proteins subjected to quantitation of -adducin after Western blotting. Data are derived from 3 animals.

Effect of Ang II on -Adducin in Neuronal Cultures
Neuronal cells in primary culture have been used to demonstrate those cellular and molecular changes in the brain that are linked to a hypertensive state from those that are induced by high BP.^2,19 Because these cultures are prepared from 1-day-old prehypertensive rats, changes induced as a result of high BP are easily eliminated in the culture.^2,19 Neuronal cultures were treated on a long-term basis with 100 nmol/L Ang II for 4 hours. This resulted in a 70% decrease in the levels of -adducin (Figure 3). Co-incubation with 1 µmol/L losartan completely the attenuated the Ang II-induced decrease in this protein. Losartan alone did not have significant effect on the basal levels of neuronal -adducin. Similarly, 1 µmol/L PD123319, an AT2 receptor antagonist, showed little effect on Ang II-induced decrease in -adducin. These data indicated that Ang II-induced decrease in -adducin is mediated by activation of AT₁ receptor subtype.

View larger version (16K): [in this window] [in a new window]   Figure 3. Effect of Ang II on -adducin levels in WKY-rat brain neuronal cultures. Neuronal cells from WKY rats were established in primary culture as described in Methods. Cultures were treated with PBS (C) 100 nmol/L Ang II (Ang II), or 100 nmol/L Ang II containing 1 µmol/L losartan (Los), 1µmol/L losartan alone, or 100 nmol/L Ang II with 1 µmol/L PD123319 (Ang II + PD) for 4 hours at 37°C. Proteins were isolated and subjected to Western blotting for -adducin as described in Methods. A, Representative autoradiogram. B, Quantiation of -adducin band.

	Discussion

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The most significant conclusion of the present study is that it provides a conceptual support for our previous hypothesis that a decreased expression of -adducin in the brain is linked to hypertension.⁶ We believe that it was critical to validate this concept with the use of nongenetic rat models of hypertension. This gene appears to provide a novel target for the central control of hypertension.

Ang II infusion and DOCA-salt rats provide ideal models for validation, because the CNS also plays a critical role in the development and establishment of hypertension in these models, as has been shown for the SHR and renin transgenic (Ren-2) rats.^23–26 Consistent with our hypothesis, we found that induction of a hypertensive state was associated with a decrease in the levels of hypothalamic -adducin. However, in contrast to genetic models, -adducin levels in the brainstem did not change in both nongenetic rat models. The physiological relevance of this difference remains speculative at the present time. It may be that the decrease in -adducin in the hypothalamic nuclei is an initial event directing the dysregulation of the CNS mechanisms leading to hypertension. However, a prolonged hypertensive state, seen only in the genetic models, may induce secondary alterations associated with a decrease in the brainstem -adducin. Alternatively, the difference could simply be genetic versus non-genetic. Irrespective of the mechanisms, it is evident that the regulation of -adducin in the hypothalamus seems to be key in the expression of hypertension. Further studies will be needed to identify the specific hypothalamic nuclei responsible for this decrease for selective gene targeting.

It has been well established that the brain renin–angiotensin system plays a critical role in the neural control of BP and that its dysregulation is one of the mechanisms that contribute to hypertension.^2,27 These observations coupled with our data beg the following question: Is -adducin a relay gene that translates dysregulated renin–angiotensin system into a hypertensive state? Our data suggest this possibility: (1) the brain renin–angiotensin system is shown to contribute to hypertension in all four rat models;^2,23–27 (2) neuronal cultures from prehypertensive SHR brain exhibit a decrease in -adducin expression, an increase in AT₁ receptors, and an increase in the neuromodulatory actions of Ang II;⁶ (3) long-term exposure of neuronal cultures to Ang II causes a decrease in -adducin; and (4) attenuation of hypertension by losartan prevents a decrease in -adducin in the hypothalamus.

Finally, we believe that the ability of -adducin to regulate cardiovascular functions is imprinted in the multifunctional properties of this protein.⁷ Thus, it is tempting to suggest that a following sequence of events leads to a hypertensive state. A decrease in -adducin would reduce its overall cellular activity by decreasing its interactions with both and ß subunits of adducins.⁷ It is known that heterodimerization of adducins is needed for their activity.⁷ A reduction in its activity would be translated into alterations in the activation of key protein kinases such as MARCKS and a subsequent modulation of the neuronal cytoskeleton. These would, in turn, modulate vesicular transport and increase the release of neurotransmitters/neuromodulators, thus stimulating neuronal activity. Increased neuronal activity would be a key cellular change that would relay adducin to signal downstream in the form of an increased sympathetic nerve activity and other dysregulated cardiovascular functions in hypertension. Some evidence to support this cascade of events are (1) levels of adducins regulate cellular and cytoskeletal activities including Ca²⁺ influx;⁷ (2) a decrease in adducin is demonstrated to stimulate Na⁺/K⁺ pump activity, which would be key in the stimulation of neuronal activity;^6,7 (3) MARCKS phosphorylation has been shown to stimulate vesicular transport in neurons;²⁸ and (4) -adducin directly influences neuronal activity.⁷

In conclusion, our studies support that a decrease in the expression of hypothalamic -adducin is linked to neurogenic hypertension. However, functional studies are needed to establish a cause-and-effect relationship between -adducin decreases and development of hypertension. This leaves open the possibility that -adducin may be a marker rather than a cause of neurogenic hypertension.

Perspectives
Adducin is a cytosolic protein with multifunctional properties. They include vesicular transport, Ca²⁺ mobilization, cytoskeletal reorganization, Na⁺/K⁺ ATPase regulation, and neuronal activity. Thus, adducin is ideally poised to be a key player in the central control of cardiovascular functions. This suggestion is supported by our earlier data that a decrease in the brain -adducin subtype is associated with hypertension in genetic rat models. The significance of our present findings is that it provides conceptual support for our hypothesis. Hypothalamic decrease of this gene could be responsible for hypertension in genetic and nongenetic models. This puts us in a unique position to determine if normalization of -adducin expression by gene transfer/manipulation techniques would prevent neurogenic hypertension on a long-term basis.

	Acknowledgments

 
We thank Nichole Herring for her assistance in the preparation of this manuscript and Fan Lin for the preparation of neuronal cultures. This work was supported by National Institutes of Health grants HL33610 and HL56921.

	Footnotes

 
H.Y.’s current affiliation is Tularik Inc., San Francisco, Calif.

Received September 29, 2003; first decision November 18, 2003; accepted December 4, 2003.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 43/2/324    most recent 01.HYP.0000113045.12850.cdv1 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 Yang, H. Articles by Raizada, M. K. Search for Related Content PubMed PubMed Citation Articles by Yang, H. Articles by Raizada, M. K. Related Collections Animal models of human disease Other hypertension Genomics Genetics of cardiovascular disease