scholarly journals Possible role of brain salt-inducible kinase 1 in responses to central sodium in Dahl rats

2012 ◽  
Vol 303 (2) ◽  
pp. R236-R245 ◽  
Author(s):  
Bing S. Huang ◽  
Roselyn A. White ◽  
Frans H. H. Leenen
Keyword(s):  
Protein Kinase ◽  
Wistar Rats ◽  
Kinase Inhibitor ◽  
Specific Protein ◽  
Ang Ii ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
Pressor Responses ◽  
Protein Kinase C Inhibitor

In Dahl salt-sensitive (S) rats, Na+ entry into the cerebrospinal fluid (CSF) and sympathoexcitatory and pressor responses to CSF Na+ are enhanced. Salt-inducible kinase 1 (SIK1) increases Na+/K+-ATPase activity in kidney cells. We tested the possible role of SIK1 in regulation of CSF [Na+] and responses to Na+ in the brain. SIK1 protein and activity were lower in hypothalamic tissue of Dahl S (SS/Mcw) compared with salt-resistant SS.BN13 rats. Intracerebroventricular infusion of the protein kinase inhibitor staurosporine at 25 ng/day, to inhibit SIK1 further increased mean arterial pressure (MAP) and HR but did not affect the increase in CSF [Na+] or hypothalamic aldosterone in Dahl S on a high-salt diet. Intracerebroventricular infusion of Na+-rich artificial CSF caused significantly larger increases in renal sympathetic nerve activity, MAP, and HR in Dahl S vs. SS.BN13 or Wistar rats on a normal-salt diet. Intracerebroventricular injection of 5 ng staurosporine enhanced these responses, but the enhancement in Dahl S rats was only one-third that in SS.BN13 and Wistar rats. Staurosporine had no effect on MAP and HR responses to intracerebroventricular ANG II or carbachol, whereas the specific protein kinase C inhibitor GF109203X inhibited pressor responses to intracerebroventricular Na+-rich artificial CSF or ANG II. These results suggest that the SIK1-Na+/K+-ATPase network in neurons acts to attenuate sympathoexcitatory and pressor responses to increases in brain [Na+]. The lower hypothalamic SIK1 activity and smaller effect of staurosporine in Dahl S rats suggest that impaired activation of neuronal SIK1 by Na+ may contribute to their enhanced central responses to sodium.

Abstract 422: Role of Brain Salt-inducible Kinase 1 in Responses to Central Sodium in Salt-induced Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Bing S Huang ◽  
Roselyn A White ◽  
Frans H Leenen
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Specific Protein ◽  
Feedback Mechanism ◽  
Ang Ii ◽  
High Salt Diet ◽  
Pressor Responses ◽  
Induced Hypertension ◽  
Protein Kinase C Inhibitor

In Dahl salt sensitive (S) rats, sympatho-excitatory and pressor responses to CSF Na + are enhanced. Salt-inducible kinase 1 (SIK1) increases Na + /K + -ATPase activity in kidney cells. We tested the possible role of SIK1 in regulation of sympatho-excitatory and pressor responses to Na + in the brain. Icv injection of the protein kinase inhibitor staurosporine (staur, 5ng) to inhibit SIK1 similarly enhanced renal sympathetic nerve activity (RSNA), BP and HR responses to icv infusion of Na + -rich aCSF in Wistar and salt-resistant Dahl SS.BN13. The enhancement in Dahl S rats was only 1/3 of that in other strains. Staur had no effect on BP responses to icv Ang II or carbachol, whereas the specific protein kinase C inhibitor GF109203X attenuated pressor responses to icv Na + -rich aCSF or Ang II. Hypothalamic SIK1 protein and activity, measured by Western blot and phosphocellulose binding technique, were lower in Dahl S vs SS.BN13 rats after high salt diet for 2 weeks. Staur at 5-50 nM inhibited SIK1 activity in a dose-related manner. These data suggest that the SIK1 -Na + /K + -ATPase network in neurons acts as a feedback mechanism to attenuate sympatho-excitatory and pressor responses to increases in brain [Na + ]. Lower neuronal SIK1 protein expression and activity in Dahl S rats may contribute to enhanced responses to CSF Na + and thereby to their salt-induced hypertension. Data= means±SE (n=4-7). * p<0.05, vs. SS.BN13 or Wistar rats.

scholarly journals Evidence for a role of protein kinase C in hypoxic pulmonary vasoconstriction

1999 ◽  
Vol 276 (1) ◽  
pp. L90-L95 ◽  
Author(s):  
Norbert Weissmann ◽  
Robert Voswinckel ◽  
Thorsten Hardebusch ◽  
Simone Rosseau ◽  
Hossein Ardeschir Ghofrani ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nadph Oxidase ◽  
Superoxide Anion ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Ang Ii ◽  
Pkc Inhibitor ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation, thus optimizing gas exchange. NADPH oxidase-related superoxide anion generation has been suggested as part of the signaling response to hypoxia. Because protein kinase (PK) C activation can occur during hypoxia and PKC activation is known to be critical for NADPH oxidase stimulation in different cell types, we probed the role of PKC in hypoxic vasoconstriction in intact rabbit lungs. Control vasoconstrictor responses were elicited by angiotensin II (ANG II) and the stable thromboxane analog U-46619. Portions of the experiments were performed while NO synthesis and prostanoid generation were blocked with N G-monomethyl-l-arginine and acetylsalicylic acid to avoid confounding effects due to interference with these vasoactive mediators. The PKC inhibitor H-7 (10–50 μM) caused dose-dependent inhibition of HPV, but this agent lacked specificity because ANG II- and U-46619-induced vasoconstrictions were correspondingly suppressed. In contrast, low concentrations of the specific PKC inhibitor bisindolylmaleimide I (BIM; 1–15 μM) strongly inhibited the hypoxic vasoconstriction without any interference with the responses to the pharmacological agents. Superimposable dose-inhibition curves were also obtained for BIM when lung NO synthesis and prostanoid generation were blocked throughout the experiments. Under either condition, BIM did not affect normoxic vascular tone. The PKC activator farnesylthiotriazole (FTT), ascertained to stimulate rabbit NADPH oxidase by provocation of alveolar macrophage superoxide anion generation in vitro, caused rapid-onset, transient pressor responses in normoxic lungs. After FTT, the hypoxic vasoconstrictor response was totally suppressed, in contrast to the largely maintained pressor responses to ANG II and U-46619. The lungs became refractory even to delayed hypoxic challenges after FTT application. In conclusion, these data support the concept that activation of PKC is involved in the transduction pathway forwarding pulmonary vasoconstriction in response to alveolar hypoxia.

Mechanisms in the PVN mediating local and central sodium-induced hypertension in Wistar rats

2009 ◽  
Vol 296 (3) ◽  
pp. R618-R630 ◽  
Author(s):  
Alexander Gabor ◽  
Frans H. H. Leenen
Keyword(s):  
Wistar Rats ◽  
Ouabain Binding ◽  
Short Term ◽  
Receptor Stimulation ◽  
Intracerebroventricular Infusion ◽  
Artificial Cerebrospinal Fluid ◽  
Pressor Responses ◽  
Induced Hypertension

Sympathoexcitatory and hypertensive responses to central infusion of Na+-rich artificial cerebrospinal fluid (aCSF) are enhanced by aldosterone and mediated by mineralocorticoid receptors (MRs) and benzamil-blockable Na+ influx, leading to “ouabain” release and ANG II type 1 (AT1) receptor stimulation. The present study evaluated the functional role of these mechanisms in the paraventricular nucleus (PVN). In conscious Wistar rats, Na+-rich aCSF was infused either directly into the PVN or intracerebroventricularly preceded by aldosterone and blockers. Infusion of Na+-rich aCSF in the PVN caused gradual increases in blood pressure (BP) and heart rate (HR). Aldosterone and a subpressor dose of ouabain in the PVN alone did not affect BP and HR but enhanced responses to Na+. Eplerenone, benzamil, and “ouabain”-binding Fab fragments only blocked the enhancement by aldosterone, whereas losartan blocked all responses to Na+-rich aCSF in the PVN. Increases in BP and HR by intracerebroventricular infusion of Na+-rich aCSF were enhanced by aldosterone infused intracerebroventricularly, but not in the PVN. Telmisartan in the PVN again blocked all responses. In contrast, both eplerenone and benzamil in the PVN did not change the pressor responses to intracerebroventricular infusion of aldosterone and Na+-rich aCSF. These findings indicate that AT1 receptors in the PVN mediate the responses to Na+-rich aCSF and their enhancement by aldosterone, both locally in the PVN or in the general CSF. MRs, benzamil-blockable Na+ channels or transporters, and “ouabain” can be functionally active in the PVN, but in Wistar rats appear not to contribute to the pressor responses to short-term increases in CSF [Na+].

Central neuronal activation and pressor responses induced by circulating ANG II: role of the brain aldosterone-“ouabain” pathway

2010 ◽  
Vol 299 (2) ◽  
pp. H422-H430 ◽  
Author(s):  
Bing S. Huang ◽  
Sara Ahmadi ◽  
Monir Ahmad ◽  
Roselyn A. White ◽  
Frans H. H. Leenen
Keyword(s):  
Mineralocorticoid Receptor ◽  
Pressor Response ◽  
Plasma Aldosterone ◽  
Receptor Blocker ◽  
Ang Ii ◽  
Neuronal Activation ◽  
Intracerebroventricular Infusion ◽  
Pressor Responses ◽  
Hypothalamic Nuclei

An increase in plasma ANG II causes neuronal activation in hypothalamic nuclei and a slow pressor response, presumably by increasing sympathetic drive. We evaluated whether the activation of a neuromodulatory pathway, involving aldosterone and “ouabain,” is involved in these responses. In Wistar rats, the subcutaneous infusion of ANG II at 150 and 500 ng·kg−1·min−1 gradually increased blood pressure up to 60 mmHg at the highest dose. ANG II at 500 ng·kg−1·min−1 increased plasma ANG II by 4-fold, plasma aldosterone by 25-fold, and hypothalamic aldosterone by 3-fold. The intracerebroventricular infusion of an aldosterone synthase (AS) inhibitor prevented the ANG II-induced increase in hypothalamic aldosterone without affecting the increase in plasma aldosterone. Neuronal activity, as assessed by Fra-like immunoreactivity, increased transiently in the subfornical organ (SFO) but progressively in the paraventricular nucleus (PVN) and supraoptic nucleus (SON). The central infusion of the AS inhibitor or a mineralocorticoid receptor blocker markedly attenuated the ANG II-induced neuronal activation in the PVN but not in the SON. Pressor responses to ANG II at 150 ng·kg−1·min−1 were abolished by an intracerebroventricular infusion of the AS inhibitor. Pressor responses to ANG II at 500 ng·kg−1·min−1 were attenuated by the central infusion of the AS inhibitor or the mineralocorticoid receptor blocker by 70–80% and by Digibind (to bind “ouabain”) by 50%. These results suggest a novel central nervous system mechanism for the ANG II-induced slow pressor response, i.e., circulating ANG II activates the SFO, leading to the direct activation of the PVN and SON, and, in addition, via aldosterone-dependent amplifying mechanisms, causes sustained activation of the PVN and thereby hypertension.

Mechanisms mediating sodium-induced pressor responses in the PVN of Dahl rats

2011 ◽  
Vol 301 (5) ◽  
pp. R1338-R1349 ◽  
Author(s):  
Alexander Gabor ◽  
Frans H. H. Leenen
Keyword(s):  
Wistar Rats ◽  
Mineralocorticoid Receptors ◽  
High Salt Diet ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
Artificial Cerebrospinal Fluid ◽  
Pressor Responses ◽  
No Release ◽  
The Brain

Intracerebroventricular infusion of Na+-rich artificial cerebrospinal fluid (aCSF) causes larger sympathetic and pressor responses in Dahl salt-sensitive (S) than -resistant (R) or Wistar rats. Enhanced activity of the aldosterone-“ouabain” pathway or decreased nitric oxide (NO) release may contribute to this enhanced responsiveness. Where in the brain these mechanisms interact is largely unknown. The present study evaluated whether Na+ in the paraventricular nucleus (PVN) causes larger pressor responses in Dahl S (SS/Mcw) than R (Dahl SS.BN13) rats and whether mineralocorticoid receptors, benzamil-blockable Na+ channels, “ouabain,” angiotensin type 1 receptors, or NO mediates these enhanced responses. Na+-rich aCSF in the PVN caused 30–40% larger increases in blood pressure and heart rate in Dahl S than R or Wistar rats, whereas responses to ouabain, ANG II, or Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME) in the PVN were the same. These responses to Na+ were not affected by eplerenone, benzamil, or Fab fragments, whereas they were fully blocked by losartan, in Dahl S and R rats. l-NAME enhanced them more in Dahl R than S rats, thereby equalizing the responses in the two strains. Pressor responses to l-NAME in the PVN were attenuated by a high-salt diet in Dahl S, but not R, rats. The results indicate that acute and chronic increases in Na+ concentration in the PVN inhibit NO release in the PVN of Dahl S, but not R, rats, thereby contributing to the enhanced pressor responses to Na+ in Dahl S rats.

Role of protein kinase C in T-cell antigen receptor regulation of p21ras: evidence that two p21ras regulatory pathways coexist in T cells

1992 ◽  
Vol 12 (7) ◽  
pp. 3305-3312
Author(s):  
M Izquierdo ◽  
J Downward ◽  
J D Graves ◽  
D A Cantrell
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Antigen Receptor ◽  
Permeabilized Cell ◽  
Regulatory Pathways ◽  
Kinase C ◽  
Stimulation Of

T-lymphocyte activation via the antigen receptor complex (TCR) results in accumulation of p21ras in the active GTP-bound state. Stimulation of protein kinase C (PKC) can also activate p21ras, and it has been proposed that the TCR effect on p21ras occurs as a consequence of TCR regulation of PKC. To test the role of PKC in TCR regulation of p21ras, a permeabilized cell system was used to examine TCR regulation of p21ras under conditions in which TCR activation of PKC was blocked, first by using a PKC pseudosubstrate peptide inhibitor and second by using ionic conditions that prevent phosphatidyl inositol hydrolysis and hence diacylglycerol production and PKC stimulation. The data show that TCR-induced p21ras activation is not mediated exclusively by PKC. Thus, in the absence of PKC stimulation, the TCR was still able to induce accumulation of p21ras-GTP complexes, and this stimulation correlated with an inactivation of p21ras GTPase-activating proteins. The protein tyrosine kinase inhibitor herbimycin could prevent the non-PKC-mediated, TCR-induced stimulation of p21ras. These data indicate that two mechanisms for p21ras regulation coexist in T cells: one PKC mediated and one not. The TCR can apparently couple to p21ras via a non-PKC-controlled route that may involve tyrosine kinases.

The protein kinase C inhibitor H-7 activates human neutrophils: effect on shape, actin polymerization, fluid pinocytosis and locomotion

1990 ◽  
Vol 96 (1) ◽  
pp. 99-106
Author(s):  
H.U. Keller ◽  
V. Niggli ◽  
A. Zimmermann ◽  
R. Portmann
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Actin Polymerization ◽  
Kinase Inhibitor ◽  
Human Neutrophils ◽  
Kinase C ◽  
Chemotactic Peptides ◽  
Protein Kinase C Inhibitor ◽  
Shape Changes ◽  
Stimulation Of

The present study demonstrates new properties of H-7. The protein kinase inhibitor H-7 is a potent activator of several neutrophil functions. Stimulation of initially spherical nonmotile neutrophils elicits vigorous shape changes within a few seconds, increases in cytoskeletal actin, altered F-actin distribution, increased adhesiveness and a relatively small increase in pinocytic activity. H-7 has also chemokinetic activities. Depending on the experimental condition, H-7 may elicit or inhibit neutrophil locomotion. It failed to induce chemotaxis. Thus, the response pattern elicited by H-7 is different from that of other leukocyte activators such as chemotactic peptides, PMA or diacylglycerols. The finding that H-7 can elicit shape changes, actin polymerization and pinocytosis suggests that these events can occur without activation of protein kinase C (PKC). PMA-induced shape changes and stimulation of pinocytosis were not inhibited by H-7.

scholarly journals Rate of calcium entry determines the rapid changes in protein kinase C activity in angiotensin II-stimulated adrenal glomerulosa cells

1994 ◽  
Vol 297 (3) ◽  
pp. 523-528 ◽  
Author(s):  
I Kojima ◽  
N Kawamura ◽  
H Shibata
Keyword(s):  
Protein Kinase C ◽  
Angiotensin Ii ◽  
Protein Kinase ◽  
Specific Substrate ◽  
Ang Ii ◽  
Kinase C ◽  
Aldosterone Production ◽  
Glomerulosa Cells ◽  
Peptide Phosphorylation

The present study was conducted to monitor precisely the activity of protein kinase C (PKC) in adrenal glomerulosa cells stimulated by angiotensin II (ANG II). PKC activity in cells was monitored by measuring phosphorylation of a synthetic KRTLRR peptide, a specific substrate for PKC, immediately after the permeabilization of the cells with digitonin [Heasley and Johnson J. Biol. Chem. (1989) 264, 8646-8652]. Addition of 1 nM ANG II induced a gradual increase in KRTLRR peptide phosphorylation, which reached a peak at 30 min, and phosphorylation was sustained thereafter. When the action of ANG II was terminated by adding [Sar1,Ala8]ANG II, a competitive antagonist, both Ca2+ entry and KRTLRR phosphorylation ceased rapidly, whereas diacylglyercol (DAG) content was not changed significantly within 10 min. Similarly, when blockade of Ca2+ entry was achieved by decreasing extracellular Ca2+ to 1 microM or by adding 1 microM nitrendipine, KRTLRR peptide phosphorylation was decreased within 5 min. In addition, restoration of Ca2+ entry was accompanied by an immediate increase in KRTLRR peptide phosphorylation. Under the same condition, DAG content did not change significantly. We then examined the role of the PKC pathway in ANG II-induced aldosterone production. Ro 31-8220 inhibited ANG II-induced KRTLRR phosphorylation without affecting the activity of calmodulin-dependent protein kinase II. In the presence of Ro 31-8220, ANG II-mediated aldosterone production was decreased to approx. 50%. Likewise, intracellular administration of PKC19-36, a sequence corresponding to residues 19-36 of the regulatory domain of PKC known to inhibit PKC activity, attenuated ANG II-mediated activation of PKC and aldosterone output. These results indicate a critical role of Ca2+ entry in the regulation of PKC activity by ANG II.

scholarly journals Mitogen-Activated Protein Kinase Hog1 Mediates Adaptation to G1 Checkpoint Arrest during Arsenite and Hyperosmotic Stress

2008 ◽  
Vol 7 (8) ◽  
pp. 1309-1317 ◽  
Author(s):  
Iwona Migdal ◽  
Yulia Ilina ◽  
Markus J. Tamás ◽  
Robert Wysocki
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
Kinase Inhibitor ◽  
Hyperosmotic Stress ◽  
Mitogen Activated Protein Kinase ◽  
Hog Pathway ◽  
Cycle Arrest ◽  
Mitogen Activated Protein

ABSTRACT Cells slow down cell cycle progression in order to adapt to unfavorable stress conditions. Yeast (Saccharomyces cerevisiae) responds to osmotic stress by triggering G1 and G2 checkpoint delays that are dependent on the mitogen-activated protein kinase (MAPK) Hog1. The high-osmolarity glycerol (HOG) pathway is also activated by arsenite, and the hog1Δ mutant is highly sensitive to arsenite, partly due to increased arsenite influx into hog1Δ cells. Yeast cell cycle regulation in response to arsenite and the role of Hog1 in this process have not yet been analyzed. Here, we found that long-term exposure to arsenite led to transient G1 and G2 delays in wild-type cells, whereas cells that lack the HOG1 gene or are defective in Hog1 kinase activity displayed persistent G1 cell cycle arrest. Elevated levels of intracellular arsenite and “cross talk” between the HOG and pheromone response pathways, observed in arsenite-treated hog1Δ cells, prolonged the G1 delay but did not cause a persistent G1 arrest. In contrast, deletion of the SIC1 gene encoding a cyclin-dependent kinase inhibitor fully suppressed the observed block of G1 exit in hog1Δ cells. Moreover, the Sic1 protein was stabilized in arsenite-treated hog1Δ cells. Interestingly, Sic1-dependent persistent G1 arrest was also observed in hog1Δ cells during hyperosmotic stress. Taken together, our data point to an important role of the Hog1 kinase in adaptation to stress-induced G1 cell cycle arrest.

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