Up-regulation of vascular and renal mitogen-activated protein kinases in hypertensive rats is normalized by inhibitors of the Na+/Mg2+ exchanger

Touyz, Rhian M.; Yao, Guoying

doi:10.1042/cs20030033

Cited by 21 publications

(17 citation statements)

References 47 publications

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“…38 Another mechanism whereby aldosterone may influence urinary Mg 2ϩ excretion is through the Na ϩ /Mg 2ϩ exchanger, which we demonstrated to be upregulated in hypertension. 39 Hence altered Mg 2ϩ metabolism in hyperaldosteronism may be related to direct stimulation of the Na ϩ /Mg 2ϩ exchanger on the one hand and to downregulation of TRPM7 on the other.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Renal TRPM7 and Increased Inflammation and Fibrosis in Aldosterone-Infused Mice

et al. 2008

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Abstract-Hyperaldosteronism is associated with hypertension, cardiovascular fibrosis, and electrolyte disturbances, including hypomagnesemia. Mechanisms underlying aldosterone-mediated Mg 2ϩ changes are unclear, but the novel Mg 2ϩ transporters TRPM6 and TRPM7 may be important. We examined whether aldosterone influences renal TRPM6/7 and the TRPM7 downstream target annexin-1 and tested the hypothesis that Mg 2ϩ administration ameliorates aldosterone-induced cardiovascular and renal injury and prevents aldosterone-associated hypertension. C57B6 mice were studied (12 weeks, nϭ8 to 9/group); (1) control group (0.2% dietary Mg 2ϩ ), (2) Mg 2ϩ group (0.75% dietary Mg 2ϩ ), (3) aldosterone group (Aldo, 400 g/kg/min and 0.9% NaCl drinking water), and (4) AldoϩMg 2ϩ group. Blood pressure was unaltered by aldosterone and was similar in all groups throughout the experiment. Serum Na ϩ was increased and serum K ϩ and Mg 2ϩ decreased in the Aldo group. Aldo mice had hypomagnesuria and proteinuria, and renal, cardiac, and aortic fibrosis, which were normalized by Mg 2ϩ supplementation. Renal and cardiovascular expression of interleukin-6, VCAM1 and COX2 was increased in the Aldo group. Magnesium attenuated renal and cardiac interleukin-6 content and decreased renal VCAM1 and cardiac COX2 expression (PϽ0.05). Aldosterone decreased expression of renal TRPM7 and the downstream target annexin-1 (PϽ0.05) without effect on TRPM6. Whereas Mg 2ϩ increased mRNA expression of TRPM6 and TRPM7, it had no effect on TRPM7 and annexin-1 protein content. Our data demonstrate that aldosterone mediates blood pressure-independent renal and cardiovascular fibrosis and inflammation through Mg 2ϩ -sensitive pathways. We suggest that altered Mg 2ϩ metabolism in hyperaldosteronism may relate to TRPM7 downregulation and that Mg 2ϩ protects against cardiovascular and renal damaging actions of aldosterone. A ldosterone, classically thought to be produced by the zona glomerulosa of the adrenal cortex and implicated in the maintenance of sodium, potassium, and acid-base balance and blood pressure regulation, is now considered a hormone with pleiotropic actions, produced by multiple tissues, including the heart, vessels, kidney, and brain. 1,2 In addition to regulating renal electrolyte excretion, aldosterone contributes to vascular inflammation, oxidative stress, collagen deposition, and endothelial dysfunction. [3][4][5] As such, aldosterone has been implicated in the development of cardiovascular and renal remodeling, fibrosis, and injury. The importance of these processes in clinical medicine is being increasingly recognized by the cardiovascular and renal protective effects of the aldosterone antagonists, spironolactone and eplerenone. 6,7 The profibrotic and proinflammatory actions of aldosteronism are accompanied by disturbances in cation homeostasis including hypomagnesemia and decreased intracellular free magnesium concentration ([Mg 2ϩ ] i ). 8,9 Recent evidence suggests that aldosterone-induced cardiovascular inflammation is induced, in part...

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Section: Discussionmentioning

confidence: 99%

Downregulation of Renal TRPM7 and Increased Inflammation and Fibrosis in Aldosterone-Infused Mice

et al. 2008

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“…Our results are in accordance with previous studies that associate JNK activation with increased levels of oxidative stress and ROS-mediated cell death. 34 In particular, JNK is known to play a major role in cardiovascular disease and is activated on mechanical stress, hypertension, [11][12][13] and ischemia/reperfusion. 35 JNK has also been reported to be activated in advanced atherosclerotic plaques in rabbits as well as in humans 34 and to activate matrix proteases involved in disease progression of abdominal aortic aneurysm in mice and humans.…”

Section: Discussionmentioning

confidence: 99%

“…9 Studies using gene targeting as well as JNK inhibitors demonstrated the involvement of JNK1 and JNK2 genes in several pathological conditions including cancer, immune diseases, and neurological diseases as well as metabolic disorders and inflammatory conditions such as arthritis and atherosclerosis. 10 JNKs are expressed in vascular smooth muscle cells and endothelial cells and activated by a wide range of stimuli such as oxidative stress, mechanical stretch, hypertension, [11][12][13] hyperglycemia, apoptosis, 14 and inflammation. 10 A recent study suggested a role of JNK in endothelial dysfunction: short-term exposure of coronary arterioles to tumor necrosis factor-␣-induced endothelial dysfunction through activation of JNK signal transduction pathway and generation of superoxide anion.…”

Section: Clinical Perspective P 2080mentioning

confidence: 99%

c-Jun N-Terminal Kinase 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress

et al. 2008

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Background-Hypercholesterolemia-induced endothelial dysfunction due to excessive production of reactive oxygen species is a major trigger of atherogenesis. The c-Jun-N-terminal kinases (JNKs) are activated by oxidative stress and play a key role in atherogenesis and inflammation. We investigated whether JNK2 deletion protects from hypercholesterolemia-induced endothelial dysfunction and oxidative stress. Methods and Results-Male JNK2 knockout (JNK2 Ϫ/Ϫ ) and wild-type (WT) mice (8 weeks old) were fed either a high-cholesterol diet (HCD; 1.25% total cholesterol) or a normal diet for 14 weeks. Aortic lysates of WT mice fed a HCD showed an increase in JNK phosphorylation compared with WT mice fed a normal diet (PϽ0.05). Endothelium-dependent relaxations to acetylcholine were impaired in WT HCD mice (PϽ0.05 versus WT normal diet). In contrast, JNK2 Ϫ/Ϫ HCD mice did not exhibit endothelial dysfunction (96Ϯ5% maximal relaxation in response to acetylcholine; PϽ0.05 versus WT HCD). Endothelium-independent relaxations were identical in all groups. A hypercholesterolemia-induced decrease in nitric oxide (NO) release of endothelial cells was found in WT but not in JNK2 Ϫ/Ϫ mice. In parallel, endothelial NO synthase expression was upregulated only in JNK2 Ϫ/Ϫ HCD animals, whereas the expression of antioxidant defense systems such as extracellular superoxide dismutase and manganese superoxide dismutase was decreased in WT but not in JNK2 Ϫ/Ϫ HCD mice. In contrast to JNK2 Ϫ/Ϫ mice, WT HCD displayed an increase in O 2 Ϫ and ONOO Ϫ concentrations as well as nitrotyrosine staining and peroxidation. Conclusions-JNK2 plays a critical role as a mediator of hypercholesterolemia-induced endothelial dysfunction and oxidative stress. Thus, JNK2 may provide a novel target for prevention of vascular disease and atherosclerosis.

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“…In theory, such reductions in activity could be mediated by PKC and/or mitogen-activated protein kinase (MAPK) (3,19,37). Past studies have shown that both phosphotransferases are upregulated in the hypertensive state (23,36). If these signaling proteins are indeed enhanced in feed arteries from hypertensive hamsters, it is reasonable to assume that their most observable impact on cell-to-cell communication would occur under experimental conditions that ensure their robust activation.…”

Section: Hypertension and Cell-to-cell Communicationmentioning

confidence: 99%

Hypertension attenuates cell-to-cell communication in hamster retractor muscle feed arteries

Kurjiaka

Bender²,

Nye³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Hypertension attenuates cell-tocell communication in hamster retractor muscle feed arteries. Am J Physiol Heart Circ Physiol 288: H861-H870, 2005. First published October 14, 2004 doi:10.1152/ajpheart.00729.2004.-This study examined whether hypertension attenuated cell-to-cell communication in skeletal muscle resistance arteries. Briefly, arteries feeding the retractor muscle of normotensive and hypertensive hamsters were cannulated, pressurized, and superfused with a physiological saline solution. Cell-to-cell communication was functionally assessed by application of vasoactive stimuli (via micropipette) to a small portion of a feed artery while diameter at sites distal to the point of agent application was monitored. In keeping with past observations, discrete application of a smooth muscle depolarizing agent (phenylephrine or KCl) elicited a localized vasoconstriction that conducted poorly along feed arteries from normotensive hamsters. In contrast, acetylcholine, an agent known to hyperpolarize endothelial cells, elicited a vasodilation in normotensive feed arteries that conducted with little decay. Whereas smooth muscle depolarizing agents continued to elicit a localized response, conduction of endothelium-dependent vasodilation was attenuated in hypertensive hamsters. This decrease occurred in the absence of changes in vessel reactivity to intravascular pressure or to global application of phenylephrine, U-46619, or acetylcholine. We propose, on the basis of these physiological observations, quantitative mRNA measurements of connexins 37, 40, 43, and 45, and analysis of the literature, that an increase in endothelial-to-endothelial or smooth muscle-to-endothelial coupling resistance is likely responsible for hypertension-induced impairment in vascular communication. We hypothesize that this attenuation could contribute to the rise in total peripheral resistance characteristically observed in hypertension.

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Up-regulation of vascular and renal mitogen-activated protein kinases in hypertensive rats is normalized by inhibitors of the Na+/Mg2+ exchanger

Cited by 21 publications

References 47 publications

Downregulation of Renal TRPM7 and Increased Inflammation and Fibrosis in Aldosterone-Infused Mice

Downregulation of Renal TRPM7 and Increased Inflammation and Fibrosis in Aldosterone-Infused Mice

c-Jun N-Terminal Kinase 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress

Hypertension attenuates cell-to-cell communication in hamster retractor muscle feed arteries

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