Mesangial cells in glomeruli are located under a fenestrated capillary endothelium and are exposed to hydrostatic pressure necessary to sustain normal filtration (1-3). Progressive renal diseases, such as diabetic nephropathy, remnant kidney, and hypertensive nephropathy, lead to prolonged glomerular hypertension, which is involved in the mesangial cell proliferation that is considered to be the most important factor mediating glomerular sclerosis (4 -11). However, the mechanism of these changes under glomerular hypertension remains largely unknown. Hishikawa et al. (12) have reported that, in vascular smooth muscle cells, pressure promotes DNA synthesis and cell growth probably via protein kinase C (PKC), 1 although the detailed mechanism between pressure as an extracellular stimulus and proliferation is unknown.Various growth factors and mitogenic stimuli are known to induce the activation of mitogen-activated protein kinase (MAPK), a serine/threonine kinase (13,14). This kinase activity is up-regulated through phosphorylation on tyrosine and threonine residues by MAPK/extracellular signal-regulated kinase kinases (MEKs) (15, 16). MEKs are substrates for Raf-1 (17, 18), which has been reported to be activated either through receptors involved in Ras or a PKC-dependent pathway (19,20). These MAPK activators cause the translocation of MAPK from the cytosol to the nucleus (21-23), where transcription factors such as Elk-1 (24) and c-Ets (25, 26) are substrates for MAPK. This indicates that MAPK serves as an important regulator of transcriptional activity related to proliferation. Recently, Lavoie et al. (27) reported that cyclin D1 expression, which is one of the earliest cell cycle-related events to occur during the G 0 /G 1 to S phase transition, is regulated positively by MAPK. Therefore, increasing interest has been paid to the role of MAPK in the cell cycle (28 -30). We recently showed that pressure enhances G 1 /S progression and promotes the rate of DNA synthesis in mesangial cells (31). However, MAPK activation and its physiological effects in glomerular hypertension are presently unknown. We investigated MAPK activation and cell proliferation in mesangial cells using a pressure-loading apparatus. We show here that applied pressure is a novel activator of MAPK. Furthermore, we demonstrate that MAPK activation plays a role in pressure-induced proliferation, probably via cyclin D1 expression. , anti-phosphoElk-1 (Ser-383) antibody, Elk-1 fusion protein, and PD98059 (MEK EXPERIMENTAL PROCEDURES Materials
Glomerular capillary pressure is involved in the development of chronic renal failure and has at least two effects on mesangial cells: transmembrane hydrostatic pressure and stretch. To clarify whether pure hydrostatic pressure itself affects the proliferation of cultured rat mesangial cells, we compared the cell number under atmospheric pressure condition with high pressure condition. At 24 and 48 h with 0.5% serum, cell number was significantly higher under high pressure condition than under atmospheric pressure condition. At 48 h, cell number under high pressure condition was increased in a pressure-dependent manner. Furthermore, flow cytometric assay indicated that pressure-load could promote DNA synthesis rate at S phase and enhance G1/S progression induced by low concentration of serum (0.5%). These results suggest that pure hydrostatic pressure itself can promote the proliferation of cultured rat mesangial cells by advancing cell cycle progression in vitro.
Abstract-The aim of this study was to clarify the differences between the angiotensin II type 1 (AT 1 ) receptor antagonist and the angiotensin-converting enzyme (ACE) inhibitor on smooth muscle and nonmuscle myosin heavy chain isoforms in aortic smooth muscle cells of Wistar-Kyoto rats and spontaneously hypertensive rats. All 4 myosin heavy chain isoforms are heterogeneously expressed in the smooth muscle cells of the aortic tunica media in 20-week-old rats, and the contractile-type myosin heavy chains are highly expressed in smooth muscle cells of the aortic tunica media compared with the synthetic-type myosin heavy chains. Both the AT 1 receptor antagonist and the ACE inhibitor had the same effects on hemodynamics, smooth muscle cell hypertrophy and proliferation, fibrosis, and vascular remodeling in spontaneously hypertensive rats. However, the AT 1 receptor antagonist had a more potent effect on the downregulation of the synthetic-type myosin heavy chains than the ACE inhibitor in spontaneously hypertensive rat aortic tunica media. In contrast, these effects of the AT 1 receptor antagonist and the ACE inhibitor on hemodynamics, morphology, fibrosis, and expression of myosin heavy chain isoforms in smooth muscle cells of the aortic tunica media were not observed in Wistar-Kyoto rats. Thus, within 6 weeks, the AT 1 receptor antagonist might modulate the cellular composition of myosin heavy chain isoforms in smooth muscle cells more efficiently than the ACE inhibitor, without morphological changes in the spontaneously hypertensive rat aorta. (Hypertension. 1999;33:975-980.)Key Words: angiotensin Ⅲ aorta Ⅲ hypertension, arterial Ⅲ muscle, smooth Ⅲ myosin A rterial hypertension is known to result in vascular remodeling. 1 The proliferation of smooth muscle cells (SMC) is also an important component of many vascular diseases. 2,3 Rat vascular SMC contain high levels of both smooth muscle (SM) myosin heavy chain (MHC) and ␣-SM actin and very low levels of nonmuscle myosin heavy chain (NMHC). 4 In addition, they contain at least 4 MHC isoforms: SM-1 (204 kDa), SM-2 (200 kDa), NMHC-A (196 kDa), and NMHC-B (198 kDa). 5 The relative ratios between SM-MHCs and NMHCs are not only determinants of the contractile properties of SM 6 but are also a useful molecular marker for phenotypic changes in SMC. 7 The dedifferentiation process of SMC, known as phenotypic modulation, contributes to the development and/or progression of atherosclerotic diseases. 2,3 SM-MHCs have been shown to be important in the identification of differentiated SMC. 7 On the other hand, it has been demonstrated that NMHCs are most abundantly expressed in embryonic SM and proliferating SMC of arteriosclerotic lesions. 7,8 Medial hypertrophy is associated with changes in the gene expression of vascular SMC, leading to a synthetic phenotype characterized by the accumulation of NMHC. 3 Angiotensin II (Ang II) plays a key role in regulating both the tone and growth of vascular SMC and is directly involved in vascular remodeling. 9 Although Ang II interacts ...
Appropriate dosing of pilsicainide hydrochloride, an anti-arrhythmic drug excreted via the kidney, was investigated in patients on dialysis. Ten chronic hemodialysis patients with coexisting severe palpitation of supraventricular premature contractions (SVPC) were treated with 25 mg of pilsicainide hydrochloride before dialysis. All of their plasma concentrations were maintained within the therapeutic range and their mean dialysis rate was 32%. After 2 weeks, 7 patients were followed with consecutive daily dose treatment. In 3 of them, the dosage was returned to the single pre-dialysis administration because of the elevated plasma concentration reaching the toxic range 1 month after the start of administration. The dose schedule was maintained, and plasma pilsicainide concentrations remained within the therapeutic range during the 6-month follow-up. No abnormal findings were found in any parameters of electrocardiography, echocardiography or biochemistry. The number of SVPC diminished >90% compared to the pretreatment level.
he incidence of hypertension (HT) and of diabetes mellitus (DM) has been continuously increasing with the aging of society and changes in lifestyle. HT and DM can be factors in cardiac and vascular disorders, and chronic renal insufficiency (CRI), so the probability of encountering coronary artery disease in a patient with CRI is relatively high. Contrast-induced nephropathy (CIN) is defined as acute renal dysfunction manifesting as temporary elevated serum creatinine level (Scr) because of the use of a contrast agent, with no other causes, and is reversible with sufficient fluid infusion in most cases. However, there may be an irreversible disturbance. The elevation of Scr in CIN is 0.3-1.0 mg/dl or more, or by 20-50% from the previous level. 1 Recently it has become clear that renal function is an independent prognostic factor of cardiovascular diseases. 2,3 The efficacy of hemofiltration (HF) after using a contrast agent has also been indicated. However, it has been reported that hemodialysis (HD) after the administration of a contrast agent does not completely prevent complications such as CIN,5 and that CIN could not be prevented even when the area under curve of the level of contrast agent concentration decreased. 6 Contrast nephrotoxicity is believed to b temporary and furthermore, the effect on renal function over the long term is unknown. Therefore, the Circulation Journal Vol.72, March 2008effect of a contrast agent on long-term renal function was studied. Methods Study PatientsIn CIN, acute renal failure tends to occur first, and thereafter some renal insufficiency may remain. Therefore, to investigate the effect of a contrast agent on renal function in the acute phase, Scr values before the use of a contrast agent, immediately after the use of a contrast agent (max. Scr within 2 weeks after use of a contrast agent), and after use of a contrast agent in the recovery phase (within 2 months after use of a contrast agent) were recorded. Among the patients who had been administered a contrast agent from July 1997 to April 2004, those with a Scr of less than 1.2 mg/dl before the administration of a contrast agent were classified as Group N (20 patients), and those having a Scr of at least 1.2 mg/dl but less than 2.0 mg/dl before administration of a contrast agent were categorized into the following 2 groups: Group D1: 10 patients without hemodiafiltration (HDF) after use of a contrast agent, and Group D2: 15 patients with HDF after use of a contrast agent.The subjects in groups N, D1, and D2 were selected randomly. All patients gave informed consent individually before enrolling. This study was approved by the Review Committee for Clinical Research of Yamaguchi University Hospital.The background of the patients is shown in Table 1. Glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease Study (MDRD) method. 7 Scr was 0.85±0.18 mg/dl, 1.45±0.14 mg/dl, and 1.59±0.26mg/dl for Groups N, D1 and D2, respectively, and the respective GFR were 71.0±15.0ml/min, 36.8±4.1ml/min,...
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