Functional genomics as an emerging strategy for the investigation of central mechanisms in experimental hypertension

Veerasingham, Shereeni J.; Sellers, Kathleen W.; Raizada, Mohan K.

doi:10.1016/j.pbiomolbio.2003.11.007

Cited by 17 publications

(10 citation statements)

References 72 publications

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“…However, aside from inducing MIF expression, icv-injected ANG II also induces expression of many other factors and genes (40), making it difficult to ascribe any physiological changes specifically to increased MIF expression. Therefore, to produce a selective increase in neuronal MIF within the PVN, it was overexpressed via Ad5-Syn-MIF.…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor in the PVN attenuates the central pressor and dipsogenic actions of angiotensin II

Li¹,

Gao²,

Freire³

et al. 2006

FASEB j.

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Macrophage migration inhibitory factor (MIF) acts intracellularly to counteract the angiotensin (ANG) II type 1 receptor (AT1-R)-mediated chronotropic effect of ANG II in hypothalamic neurons, an effect mediated by the thiol-protein oxidoreductase (TPOR) activity of the MIF molecule. Here we determined the in vivo actions of MIF in regulating the physiological actions of ANG II that are mediated via the paraventricular nucleus (PVN), an area that serves as a relay point in the central nervous system (CNS)-mediated effects of ANG II on cardiovascular functions and water intake. Intracerebroventricular (icv) injection of ANG II into normotensive rats selectively increased MIF protein levels in the PVN and produced significant pressor and drinking responses that were inhibited by PVN administration of the AT1-R antagonist losartan. Overexpression of MIF in PVN neurons via Ad-Syn-MIF gene transfer attenuated the pressor and drinking responses produced by icv-injected ANG II. Consistently, intracellular application of MIF or MIF-(50-65) (which harbors the TPOR activity of MIF) into PVN sympathetic regulatory neurons, blunted the electrophysiological actions of ANG II at these cells. These observations establish for the first time that MIF within the PVN, acting via TPOR, is an intracellular regulator of the central cardiovascular and dipsogenic effects of ANG II.

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Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor in the PVN attenuates the central pressor and dipsogenic actions of angiotensin II

Li¹,

Gao²,

Freire³

et al. 2006

FASEB j.

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“…The sympathetic nervous (48, 91,133,198,240) and the reninangiotensin (48, 62,64,81,82,122,132,143,171,205,221) systems have been shown to be important in the pathogenesis of essential hypertension, including that associated with obesity (43). However, there are several counter-regulatory pathways (39, 76,135,142,169,174,184,205,219) (e.g., dopamine pathway), aberrations of which are involved in the pathogenesis of essential hypertension (3, 4, 8-18, 20, 21, 23-26, 29-33, 35, 37, 42, 44-46, 52-60, 67-70, 73-75, 77, 79, 80, 84, 86, 93-95, 97-103, 106-111, 114, 116, 118, 119, 124, 126-128, 130, 131, 136, 140, 141, 144-146, 148-156, 159-161, 163-166, 176-179, 182, 183, 186, 189, 192, 193, 195, 197, 203, 207, 209-216, 218, 224, 226-239), including that associated with obesity (16,37,201). Dopamine can regulate blood pressure by renal and nonrenal mechanisms (e.g., intestines and central nervous system) (93,130,131,207) that also involve the renin-angiotensin system (12,29,46,209,211,212,226,235,236).…”

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confidence: 99%

Functional genomics of the dopaminergic system in hypertension

Zeng

Sanada

Watanabe

et al. 2004

Physiological Genomics

109

172

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Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. Under normal conditions, D 1-like receptors (D1 and D5) inhibit sodium transport in the kidney and intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats (SHRs) and in humans with essential hypertension, the D 1-like receptor-mediated inhibition of epithelial sodium transport is impaired because of an uncoupling of the D1-like receptor from its G protein/effector complex. The uncoupling is receptor specific, organ selective, nephron-segment specific, precedes the onset of hypertension, and cosegregates with the hypertensive phenotype. The defective transduction of the renal dopaminergic signal is caused by activating variants of G protein-coupled receptor kinase type 4 (GRK4: R65L, A142V, A486V). The GRK4 locus is linked to and GRK4 gene variants are associated with human essential hypertension, especially in saltsensitive hypertensive subjects. Indeed, the presence of three or more GRK4 variants impairs the natriuretic response to dopaminergic stimulation in humans. In genetically hypertensive rats, renal inhibition of GRK4 expression ameliorates the hypertension. In mice, overexpression of GRK4 variants causes hypertension either with or without salt sensitivity according to the variant. GRK4 gene variants, by preventing the natriuretic function of the dopaminergic system and by allowing the antinatriuretic factors (e.g., angiotensin II type 1 receptor) to predominate, may be responsible for salt sensitivity. Subclasses of hypertension may occur because of additional perturbations caused by variants of other genes, the quantitative interaction of which may vary depending upon the genetic background. dopamine; D 1 dopamine receptor; G protein-coupled receptor kinase type 4 THE LONG-TERM REGULATION of blood pressure rests on renal and nonrenal mechanisms (22, 34, 41,82,85,138,143,172). The sympathetic nervous (48,91,133,198,240) and the reninangiotensin (48,62,64,81,82,122,132,143,171,205,221) systems have been shown to be important in the pathogenesis of essential hypertension, including that associated with obesity (43). However, there are several counter-regulatory pathways (39,76,135,142,169,174,184,205,219) (e.g., dopamine pathway), aberrations of which are involved in the pathogenesis of essential hypertension (3, 4, 8-18, 20, 21, 23-26, 29-33, 35, 37, 42, 44-46, 52-60, 67-70, 73-75, 77, 79, 80, 84, 86, 93-95, 97-103, 106-111, 114, 116, 118, 119, 124, 126-128, 130, 131, 136, 140, 141, 144-146, 148-156, 159-161, 163-166, 176-179, 182, 183, 186, 189, 192, 193, 195, 197, 203, 207, 209-216, 218, 224, 226-239), including that associated with obesity (16, 37,201). Dopamine can regulate blood pressure by renal and nonrenal mechanisms (e.g., intestines and central nervous system) (93,130,131,207) that also involve the renin-angiotensin system (12, 29, 46,209,211,212,226,235,236).Because the kidney is important in the long-term regu...

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“…2,5 These studies have demonstrated that the expression of gammaadducin (␥-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.…”

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confidence: 99%

Decrease in Hypothalamic Gamma Adducin in Rat Models of Hypertension

et al. 2004

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Abstract-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 Ⅲ hypertension Ⅲ brain Ⅲ hypothalamus T he 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][3][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 gammaadducin (␥-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 ϩ /K ϩ 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...

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Functional genomics as an emerging strategy for the investigation of central mechanisms in experimental hypertension

Cited by 17 publications

References 72 publications

Macrophage migration inhibitory factor in the PVN attenuates the central pressor and dipsogenic actions of angiotensin II

Macrophage migration inhibitory factor in the PVN attenuates the central pressor and dipsogenic actions of angiotensin II

Functional genomics of the dopaminergic system in hypertension

Decrease in Hypothalamic Gamma Adducin in Rat Models of Hypertension

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