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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progressive renal diseases lead to prolonged glomerular hypertension, which induces the proliferation of mesangial cells. This proliferation is thought to be involved in the development of renal injury. Here we investigate mitogen-activated protein kinase (MAPK) activation and cell proliferation in mesangial cells under conditions of high pressure. After pressure-load, the phosphorylation level of MAPK (at Tyr-204) increases rapidly with a peak at 1 min, although the amount of MAPK remains almost constant during pressure-load. To confirm the activation of MAPK, we carried out an immunoprecipitation-kinase assay. MAPK activity during pressure-load shows kinetics similar to that of the tyrosine phosphorylation. In contrast, c-Jun N-terminal kinase 1 (JNK1) phosphorylation falls below basal levels in response to high pressure. Immunocytochemical observations show phosphorylated MAPK in the nucleus at 10 min. The expression of c-Fos, a nuclear transcription factor, is induced by high pressure, and the induction is significantly inhibited by PD98059 (50 microM), an upstream MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitor of MAPK. The expression of the c-Jun that is induced by JNK1 activation remains unchanged during pressure-load. MAPK phosphorylation and cell proliferation by applied pressure are significantly inhibited by genistein, a tyrosine kinase inhibitor in a dose-dependent manner, but not by protein kinase C inhibitors, chelerythrine and GF109203X. Genistein also blocks pressure-induced tyrosine phosphorylation of proteins with molecular masses of 35, 53, and 180 kDa. To clarify the physiological role in MAPK activation under high pressure conditions, we transfected antisense MAPK DNA into mesangial cells. The antisense DNA (2 microM) inhibited MAPK expression by 80% compared with expression in the presence of sense or scrambled DNA, and significantly blocked pressure-induced cell proliferation. Treatment of cells with MEK inhibitor also produced a similar result. MEK inhibitor strongly suppresses DNA synthesis induced by pressure-load. Cyclin D1 expression is significantly increased under high pressure conditions, and the increase is blocked by treatment with MEK inhibitor. These findings show that pressure-load, a novel activator of MAPK, induces the activation of tyrosine kinases, and enhances the proliferation of mesangial cells, probably through cyclin D1 expression.
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PMID:Applied pressure enhances cell proliferation through mitogen-activated protein kinase activation in mesangial cells. 964 52

In cardiac fibroblasts, angiotensin II (Ang II) induced a rapid increase in extracellular signal regulated kinase (ERK) activity in a pertussis toxin insensitive manner. This ERK activation was abolished by the Gq-associated phospholipase C inhibitor U73122 but was insensitive to protein kinase C (PKC) inhibitors or PKC downregulation by phorbol ester. Intracellular Ca2+ chelation by BAPTA-AM or TMB-8 abolished Ang II induced ERK activation, whereas treatment with EGTA or nifedipine did not affect it. Ca2+ ionophore A23187 also induced a rapid increase in ERK activity to an extent similar to that of Ang II stimulation. Calmodulin inhibitors (W7 and calmidazolium) and tyrosine kinase inhibitors (genistein and ST638) completely blocked ERK activation by Ang II and A23187. Both Ang II and A23187 caused a rapid increase in the binding of GTP to p21(Ras), which was nearly abolished by genistein and calmidazolium. Transfection with the dominant negative mutant of Ras and the Ras inhibitor manumycin completely inhibited Ang II induced ERK activation. It was also found for the first time that cardiac fibroblasts abundantly expressed Ca2+-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK and that Ang II markedly induced its activation in a Ca2+/calmodulin-sensitive manner. Overexpression of the dominant negative mutant of Pyk2 significantly attenuated Ang II or A23187-induced ERK activities (36% and 38% inhibition compared with that in mock-transfected cells, respectively) and ERK tyrosine phosphorylation levels, as well as an increase in the binding of GTP to p21(Ras). These findings demonstrate that in cardiac fibroblasts, Ang II induced Ras/ERK activation is dominantly regulated by Gq-coupled Ca2+/calmodulin signaling and that Pyk2 plays an important role in the signal transmission for efficient activation of the Ang II induced Ras/ERK pathway.
Hypertension 1998 Oct
PMID:Role of calcium-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK in angiotensin II induced Ras/ERK signaling. 977 61

Monocyte infiltration into the vessel wall, a key initial step in the process of atherosclerosis, is mediated in part by monocyte chemoattractant protein-1 (MCP-1). Hypertension, particularly in the presence of an activated renin-angiotensin system, is a major risk factor for the development of atherosclerosis. To investigate a potential molecular basis for a link between hypertension and atherosclerosis, we studied the effects of angiotensin II (Ang II) on MCP-1 gene expression in rat aortic smooth muscle cells. Rat smooth muscle cells treated with Ang II exhibited a dose-dependent increase in MCP-1 mRNA accumulation that was prevented by the AT1 receptor antagonist losartan. Ang II also activated MCP-1 gene transcription. Inhibition of NADH/NADPH oxidase, which generates superoxide and H2O2, with diphenylene iodonium or apocynin decreased Ang II-induced MCP-1 mRNA accumulation. Induction of MCP-1 gene expression by Ang II was inhibited by catalase, suggesting a second messenger role for H2O2. The tyrosine kinase inhibitor genistein and the mitogen-activated protein kinase kinase inhibitor PD098059 inhibited Ang II-induced MCP-1 gene expression, consistent with a mitogen-activated protein kinase-dependent signaling mechanism. Ang II may thus promote atherogenesis by direct activation of MCP-1 gene expression in vascular smooth muscle cells.
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PMID:Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. 979 45

Insulin action starts with binding to a membrane receptor (insulin receptor-tyrosine kinase) and with activating an insulin receptor substrate 1 (IRS-1) and substrate 2 (IRS-2). Insulin receptors interact at least with three cascade reactions, phosphorylating G proteins and IRS-1, that activate PLC "ras" and PI-3-K. NIDDM can be defined as a disease caused by defective transduction of insulin signals and IR as a complex phenotype manifesting itself, emphasized by individual and environmental factors, in the cellular systems of signal transduction. IRS is a syndrome characterized by NIDDM, hypertension, visceral obesity, CHD: the X syndrome. Up to day the described mutations of the insulin-receptor gene are rare (e.g. the leprechaunism): genetic IR. Obesity is the principal cause of IR by receptorial and post-receptorial defects: metabolic IR. The obese skeletal muscle shows a reduction of insulin receptor and IRS-1 phosphorylation and of PI-3-K activation; the scarce expression of these proteins would determine the muscular IR. IR is a pattern of essential hypertension. Hypertension, dyslipidemia and abnormality of glucose metabolism are linked by IR. The so called high erythrocyte Na(+)-Li+ counter-transport is a new biochemical marker for IR and hypertension. These drugs can reduce IR: metformin, sulphonilureas, fibrats, dexfenfluramine, troglitazone, doxazosin, ACE-inhibitors.
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PMID:[Insulin resistance. Receptor and post-receptor abnormalities]. 984 54

-Protein tyrosine phosphorylation induced by arachidonic acid (AA), an important lipid second messenger, was investigated in rabbit renal proximal tubule epithelial cells. AA stimulated tyrosine phosphorylation of a number of proteins with estimated molecular weights of 42, 44, 52, 56, 85, and 170/180 kDa. The phosphoproteins pp44 and pp42 were identified as 2 isoforms of mitogen-activated protein kinase (MAPK). Phosphorylation of MAPK in response to AA was transient, dose-dependent, and accompanied by an increase in its activity. The mechanism of AA-induced MAPK activation in RTE cells was protein kinase C-independent and involved tyrosine phosphorylation of adaptor protein Shc and its association with Grb2-Sos complex. Moreover, stimulation of RTE cells with AA resulted in significant phosphorylation of epidermal growth factor (EGF) receptor and its association with Shc. The effect of AA on EGF receptor phosphorylation, its association with Shc, and MAPK activation was similar to the effect of 1 ng/mL EGF. Tyrphostin AG1478, a specific inhibitor of EGF receptor tyrosine kinase activity, completely blocked the effects of AA and EGF but not phorbol ester on MAPK phosphorylation. These data suggest that in renal tubular epithelial cells, the mechanism of AA-induced MAPK activation involves tyrosine phosphorylation of EGF receptor and its association with Shc and Grb2-Sos complex. Given the critical role of AA in signaling linked to G protein-coupled receptors (GPCRs), these observations provide a mechanism for cross talk between GPCRs linked to phospholipases and the tyrosine kinase receptor signaling cascades.
Hypertension 1998 Dec
PMID:Arachidonate-induced tyrosine phosphorylation of epidermal growth factor receptor and Shc-Grb2-Sos association. 985 79

In this review, the signal events regulated by angiotensin II (AngII) in vascular smooth muscle are analyzed based on activation of specific tyrosine kinases. AngII has been shown to play a critical role in the pathogenesis of hypertension, inflammation, atherosclerosis, and congestive heart failure. The expanding role of AngII indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Although at least three AngII receptors have been characterized, it seems that the AngII type I receptor (AT1R) is physiologically most important since pharmacologic inhibitors of the AT1R block most AngII signal events and have beneficial effects on cardiovascular disease. The AT1R is a seven transmembrane-spanning G protein-coupled receptor that regulates intracellular signal events by activation of Gq and Gi. However, many recent data indicate that activation of tyrosine kinases by several different mechanisms contributes to AngII effects in target tissues. Tyrosine kinases activated by AngII include c-Src, focal adhesion kinase (FAK), Pyk2 (CADTK), Janus kinases (JAK2 and TYK2), and the receptor tyrosine kinases Ax1, epidermal growth factor, and platelet-derived growth factor. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of paxillin, Shc, Raf, and phospholipase C-gamma after AngII stimulation. These AngII-regulated tyrosine kinases seem to be required for AngII effects such as vasoconstriction, proto-oncogene expression, and protein synthesis based on studies with tyrosine kinase inhibitors. Thus, understanding AngII-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. 989 42

-PYK2, a recently identified Ca2+-sensitive tyrosine kinase, has been implicated in extracellular signal-regulated kinase (ERK) activation via several G protein-coupled receptors. We have reported that angiotensin II (Ang II) induces Ca2+-dependent transactivation of the epidermal growth factor receptor (EGFR) which serves as a scaffold for preactivated c-Src and downstream adaptors (Shc/Grb2), leading to ERK activation in cultured rat vascular smooth muscle cells (VSMC). Herein we demonstrate the involvement of PYK2 in this cascade. Ang II rapidly induced tyrosine phosphorylation of PYK2, whose effect was completely inhibited by an AT1 receptor antagonist and an intracellular Ca2+ chelator. A Ca2+ ionophore also induced PYK2 tyrosine phosphorylation to a level comparable with that by Ang II, whereas phorbol ester-induced phosphorylation was less than that by Ang II. Moreover, PYK2 formed a complex coprecipitable with catalytically active c-Src after Ang II stimulation. Although a selective EGFR kinase inhibitor completely abolished Ang II-induced recruitment of Grb2 to EGFR and markedly attenuated Ang II-induced ERK activation, it had no effect on Ang II-induced PYK2 tyrosine phosphorylation or its association with c-Src and Grb2. These data suggest that the AT1 receptor uses Ca2+-dependent PYK2 to activate c-Src, thereby leading to EGFR transactivation, which preponderantly recruits Grb2 in rat VSMC.
Hypertension 1999 Jan
PMID:Involvement of PYK2 in angiotensin II signaling of vascular smooth muscle cells. 993 Nov 5

The present study examined the hypothesis that activation of protein kinase C (PKC), components of the mitogen-activated protein (MAP) kinase pathway, or both contributes to the inhibitory effects of 20-hydroxyeicosatetraenoic acid (20-HETE) on K+-channel activity and its vasoconstrictor response in renal arterioles. 20-HETE (0.1 to 50 micromol/L) dose-dependently produced a 30% increase in PKC activity and a fivefold rise in the expression of active extracellular signal-regulated kinase 1 (ERK1) and ERK2 proteins in renal microvessels. 20-HETE (0.01 to 1 micromol/L) reduced the diameter of isolated perfused renal interlobular arterioles by 33+/-2%. Blockade of PKC activity with an N-myristoylated PKC pseudosubstrate inhibitor (Myr-PKCi, 100 micromol/L) or calphostin C (0.5 micromol/L) had no significant effect on the vasoconstrictor response to 20-HETE. In contrast, the tyrosine kinase inhibitors genistein (30 micromol/L) and tyrphostin 25 (10 micromol/L) reduced the response to 20-HETE by 76.5+/-2.1% and 67.5+/-1.8%, respectively. A specific inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK), PD98059, had no effect on the vasoconstrictor response to 20-HETE. In cell-attached patches on renal vascular smooth muscle cells, 20-HETE reduced the open state probability of a large-conductance K+ channel (from 0.0026+/-0.0004 to 0.0006+/-0.0001). The Myr-PKCi (100 micromol/L) did not alter the inhibitory effects of 20-HETE on this channel. In contrast, the tyrosine kinase inhibitor genistein (30 micromol/L) blocked the inhibitory effects of 20-HETE on the large-conductance K+ channel. These data suggest that 20-HETE activates the MAP kinase system in renal arterioles and that the activation of a tyrosine kinase, which is proximal to MEK in this cascade, contributes to the inhibitory effects of 20-HETE on K+-channel activity and its vasoconstrictor effects in the renal arterioles.
Hypertension 1999 Jan
PMID:Role of tyrosine kinase and PKC in the vasoconstrictor response to 20-HETE in renal arterioles. 993 Nov 39

We have tested the hypothesis that growth factor signaling pathways are augmented in hypertension, a disease associated with vascular smooth muscle cell growth. Thoracic aorta was dissected from deoxycorticosterone acetate-salt (DOCA-salt) and one kidney, one clip (1K, 1C) hypertensive rats and from sham normotensive rats for use in isolated tissue bath experiments. Systolic blood pressure was significantly higher in DOCA-salt and 1K, 1C than in normotensive sham rats: 192 +/- 7, 185 +/- 10, and 117 +/- 4 mmHg, respectively. Although virtually no contraction to epidermal growth factor (EGF) was observed in endothelium-denuded sham rat aorta [1 +/- 1% phenylephrine (PE) (10 micromol/l)-induced contraction], the maximal EGF-induced contraction was 45 +/- 7% in endothelium-denuded aorta from DOCA-salt hypertensive rats and 39 +/- 7% in aorta from 1K, 1C rats. Although slightly attenuated, a contraction to EGF was still observed in endothelium-intact aortic strips from 28-day DOCA-salt hypertensive rats. We also conducted concentration-response curves to EGF on days 1, 3, 5, 7, 14, and 21 of DOCA-salt therapy. A significant contraction to EGF in aorta from DOCA-salt rats was observed on day 14, when DOCA-salt rats had significantly higher blood pressure than sham rats: 188 +/- 6 and 122 +/- 3 mmHg, respectively. Transforming growth factor-alpha, an agonist of the EGF receptor, contracted DOCA-salt rat aorta (30 +/- 7% PE-induced contraction) but not sham aorta (3 +/- 3%). The EGF receptor tyrosine kinase inhibitor 4,5-dianilinophthalimide (10 micromol/l), the mitogen-activated protein kinase kinase inhibitor PD-098059 (10 micromol/l), and the L-type voltage-gated calcium channel inhibitor diltiazem (1 mol/l), but not the cyclooxygenase inhibitor indomethacin (10 micromol/l), virtually abolished EGF-induced contraction (85, 98, and 99% reduction, respectively). These data support a striking difference in EGF signaling between normotensive and hypertensive animals. Furthermore, they provide evidence that growth factors should be considered vasoconstrictors as well as growth modulators in hypertension.
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PMID:Epidermal growth factor: a potent vasoconstrictor in experimental hypertension. 1007 82

An excessive production of extracellular matrix (ECM) proteins in glomerular mesangial cells is considered to be responsible for the development of mesangial expansion seen in diabetic nephropathy. Mechanical stretch due to glomerular hypertension has been proposed as one of the factors leading to an increase in the production of ECM proteins in mesangial cells, but the precise mechanism of stretch-induced overproduction of ECM proteins has not been elucidated. Herein, we provide the evidence that mitogen-activated protein kinase (MAPK) may play a key role in the overproduction of fibronectin (FN) in mesangial cells exposed to mechanical stretch. MAPK, also termed extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), was activated by mechanical stretch in time- and intensity-dependent manners. Stretch-induced activation of ERK was inhibited by herbimycin A, a tyrosine kinase inhibitor, but not by GF109203X or calphostin C, the inhibitors of protein kinase C. Mechanical stretch also enhanced DNA-binding activity of AP-1, and this enhancement was inhibited by PD98059, an inhibitor of MAPK or ERK kinase (MEK). Furthermore, mechanical stretch stimulated the expression of FN mRNA followed by a significant increase in its protein accumulation. PD98059 could prevent stretch-induced increase in the expression of FN mRNA and protein. These results indicate that the activation of ERK may mediate the overproduction of ECM proteins in mesangial cells exposed to mechanical stretch, an in vitro model for glomerular hypertension seen in diabetes.
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PMID:Stretch-induced overproduction of fibronectin in mesangial cells is mediated by the activation of mitogen-activated protein kinase. 1007 62


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