N Yamaguchi

Ibaraki Prefectural University of Health Sciences, Ibaragi, Ōsaka, Japan

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Publications (50)118.21 Total impact

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    ABSTRACT: Aims Endothelin (ET)-1 is the best known potent vasoconstrictor and has been implicated in pathogenesis of sepsis-associated acute kidney injury (AKI) in human or lipopolysaccharide (LPS)-induced AKI in animal models. We have previously shown that ET-1 is highly up-regulated in renal tissues and in plasma after LPS administration. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting beta-blocker, can play an important role in ameliorating levels of LPS-induced up-regulation of renal HIF-1α -ET-1 system and inflammatory cytokines in a rat model of endotoxemia. Main methods Male Wistar rats at 8 weeks of age were either administered with: a) lipopolysaccharide (LPS) only for three hours (3 h) or b) LPS, followed by continuous administration of landiolol for 3 h; c) third group was only treated with vehicle. Key findings At 3 h after LPS administration there was: a) minimal injury in kidney tissues; b) circulatory levels of creatinine, blood urea nitrogen and NGAL increased; c) expression of inflammatory cytokines, such as TNF-α, IL-6 and iNOS increased at the level of both circulatory and renal tissues. In addition, LPS significantly induced renal expression of ET-1and HIF-1α compared to control. Finally, treatment of LPS-administered rats with landiolol for 3 h normalized elevated serum markers of renal injury, up-regulated levels of renal HIF-1α -ET-1 system with normalization of TNF-α. Significance Taken together, these data led us to conclude that landiolol ameliorates the up-regulation of HIF-1α-ET-1 system in minimally morphologically-injured kidney andnormalizes biomarkers of renal injury in early hours of endotoxemia of a rat model.
    Life Sciences 05/2014; · 2.56 Impact Factor
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    ABSTRACT: Aims Septic shock, the severe form of sepsis, is associated with development of progressive damage in multiple organs. Kidney can be injured and its functions altered by activation of coagulation, vasoactive-peptide and inflammatory processes in sepsis. Endothelin (ET)-1, a potent vasoconstrictor, is implicated in the pathogenesis of sepsis and its complications. Protease-activated receptors (PARs) are shown to play an important role in the interplay between inflammation and coagulation. We examined the time-dependent alterations of ET-1 and inflammatory cytokine, such as tumor necrosis factor (TNF)-α in kidney tissue in lipopolysaccharide (LPS)-induced septic rat model and the effects of PAR2 blocking peptide on the LPS-induced elevations of renal ET-1 and TNF-α levels. Main methods Male Wistar rats at 8 weeks of age were administered with either saline solution or LPS at different time points (1, 3, 6 and 10 hours). Additionally, we treated LPS-administered rats with PAR2 blocking peptide for three hours to assess whether blockade of PAR2 has a regulatory role on the ET-1 level in septic kidney. Key findings An increase in ET-1 peptide level was observed in kidney tissue after LPS administration time-dependently. Levels of renal TNF-α peaked (around 12-fold) at 1 hour of sepsis. Interestingly, PAR2 blocking peptide normalized the LPS-induced elevations of renal ET-1 and TNF-α levels. Significance The present study reveals a distinct chronological expression of ET-1 and TNF-α in LPS-administered renal tissues and that blockade of PAR2 may play a crucial role in treating renal injury, via normalization of inflammation, coagulation and vaso-active peptide.
    Life sciences 01/2014; · 2.56 Impact Factor
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    ABSTRACT: BACKGROUND: Prevalence of non-communicable diseases are a challenging problems among menopausal women specially in a least developed country like Bangladesh, where majority of women suffering from at least one chronic diseases after menopausal age. So, the main objective of this study was to determine the prevalence of metabolic syndrome and related risk factors in Bangladeshi pre- and post-menopausal women living in the rural setting. METHODS: This study is based on a community based cross-sectional survey among 1802 rural women aged >=15 years. Metabolic syndrome was defined according to the criteria of NCEP-ATP III. Logistic regression was used to estimate the association between menopausal status and metabolic syndrome and its components. RESULTS: Metabolic syndrome was presented in 25.6% respondents and it was more prevalent among post-menopausal (39.3%) as compared to pre-menopausal (16.8%) women. Logistic regression analysis reveals that prevalence of metabolic syndrome was 1.78 times higher in post-menopausal women than pre-menopausal women (P = 0.001). Prevalence of high blood pressure, elevated fasting blood glucose, and high triglyceride were significantly higher in post-menopausal women than pre-menopausal women (P < 0.05). However, prevalence of low high-density lipoprotein cholesterol was significantly lower in post-menopausal women than pre-menopausal women (P < 0.001). CONCLUSIONS: Metabolic syndrome seems to be a major health problem among post-menopausal women in many developing countries like Bangladesh and proper policy emphasis should be given on its prevention and control.
    BMC Research Notes 04/2013; 6(1):157.
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    ABSTRACT: Metabolic syndrome (MetS) is associated with impaired angiogenesis, a process that is chiefly regulated by vascular endothelial growth factor (VEGF) upon binding to its specific receptors, VEGF-R1 and VEGF-R2. The purpose of the present study was to assess trends or patterns in plasma levels of VEGF and its soluble receptors in subjects with (MetS) or without (non-MetS) MetS; and further examine their association with clinical or metabolic parameters using a subpopulation of South Asian country. A total of 1,802 rural Bangladeshi women aged ≥15 ye ars were studied using a population-based cross-sectional survey. Plasma levels of VEGF were found to be significantly increased (MetS vs. non-MetS: 483.9 vs. 386.9, p<0.001), whereas, the soluble forms of VEGF receptors, sVEGF-R1 and sVEGF-R2, were significantly decreased in subjects with Mets (sVEGF-R1, MetS vs. non-MetS: 512.5 vs. 631.3, p<0.001; sVEGF-R2, MetS vs. non-MetS: 9,302.8 vs. 9,787.4, p=0.004). After adjustment for age and all potential variables, multiple regression analysis revealed that plasma levels of VEGF had significant positive association with blood glucose (p = 0.019) and body mass index (p = 0.007). We also found that mean plasma levels of VEGF increased in direct proportion to levels of MetS components. The present study is the first ever to demonstrate a positive association between trends in levels of plasma VEGF and MetS using a large sample size from South Asia. The association between plasma VEGF and MetS needs further investigations in order to clearly decipher the clinical predictive value and accuracy of plasma VEGF in MetS.
    Thrombosis and Haemostasis 01/2013; 109(4). · 5.76 Impact Factor
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    ABSTRACT: Parity increases the risk for coronary heart disease; however, its association with metabolic syndrome among women in low-income countries is still unknown. This study investigates the association between parity or gravidity and metabolic syndrome in rural Bangladeshi women. A cross-sectional study was conducted in 1,219 women aged 15-75 years from rural Bangladesh. Metabolic syndrome was defined according to the standard NCEP-ATP III criteria. Logistic regression was used to estimate the association between parity and gravidity and metabolic syndrome, with adjustment of potential confounding variables. Subjects with the highest gravidity (> = 4) had 1.66 times higher odds of having metabolic syndrome compared to those in the lowest gravidity (0-1) (P trend = 0.02). A similar association was found between parity and metabolic syndrome (P trend = 0.04), i.e., subjects in the highest parity (> = 4) had 1.65 times higher odds of having metabolic syndrome compared to those in the lowest parity (0-1). This positive association of parity and gravidity with metabolic syndrome was confined to pre-menopausal women (P trend <0.01). Among the components of metabolic syndrome only high blood pressure showed positive association with parity and gravidity (P trend = 0.01 and <0.001). Neither Parity nor gravidity was appreciably associated with other components of metabolic syndrome. Multi parity or gravidity may be a risk factor for metabolic syndrome.
    PLoS ONE 01/2013; 8(8):e68319. · 3.53 Impact Factor
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    ABSTRACT: The Patlak plot method of measuring cerebral blood flow (CBF) to improve the repeatability and quantitative capability, by using technetium-99m ethyl cysteinate dimer (99mTc-ECD). We calculated CBF and then statistically analyzed its relationships with various hematological and biochemical parameters. There were significant statistical correlations between these clinical parameters and the measured values of mean CBF (mCBF), also between these biochemical parameters and post-acetazolamide (p-ACZ) mCBF, in terms of estimated glomerular filtration rate (eGFR), serum albumin level, red blood cell count, blood urea nitrogen level, and random blood glucose level. In addition, statistically significant correlations were found between these parameters and increased mCBF. Another significant correlation was found between cerebrovascular reserve capacity (CVR) and platelet count. Values of p-ACZ mCBF and CVR were lower in a group with HbA(1C) >7% and high blood glucose levels than in healthy subjects. In addition, values of resting mCBF and p-ACZ mCBF were lower in a group with kidney dysfunction (eGFR <30 ml/min/1.73 m2) than in subjects with normal renal function or mild dysfunction. A multiple linear regression analysis showed a correlation between resting mCBF value and eGFR. Therefore, there were correlations between CBF and the levels of these parameters of diabetes or chronic kidney disease. These results suggest that our Patlak plot modified method may be a potentially useful tool for analyzing the relationships between CBF and underlying diseases and/or the pathophysiology of CBF dysfunction. The post-ACZ ECD Patlak resting and vascular reserve (p-ACZ ECD Patlak RVR) test provides a way of detecting minor changes in CBF, which is difficult to reveal by only resting Patlak plot method, in patients with lifestyle diseases such as diabetes or chronic kidney disease. In addition, we believe that a new modified method contribute to predict risk of cerebral vascular disorders along with clinical parameters.
    Kaku igaku. The Japanese journal of nuclear medicine 11/2012; 49(4):329-40.
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    ABSTRACT: This study was conducted to standardize treatment and determine patient and renal outcome in Japanese anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis/rapidly progressive glomerulonephritis (AAV/RPGN) patients, because the prognosis of AAV/RPGN patients in Japan had been poor compared with that of other countries. The participants in this retrospective cohort study were 824 ANCA-positive RPGN patients, 705 of whom were only myeloperoxidase (MPO)-ANCA positive. Among the early-years cohort (group A; cases diagnosed between 1988 and 1998), patients frequently died due to opportunistic infection. Therefore, we recommended a reduced dose of prednisolone (oral prednisolone dose <0.8 mg/kg/day) with or without cyclophosphamide for initial treatment of Japanese RPGN patients. After this recommendation, 1-year survival of the patients improved: 75% in group A, 79% in group B (between 1999 and 2002), and 81% in group C (after 2003). During the entire observation period, average serum creatinine level at the start of treatment decreased, and improvement of 1-year renal survival was also found (72% in group A, 83% in group B, and 83% in group C), while the recurrence rate was significantly increased in group C (0.05/patient-year in group A, 0.07/patient-year in group B, and 0.13/patient-year in group C). Oral prednisolone dose <0.8 mg/kg/day with or without cyclophosphamide as an initial treatment could improve patient survival in older Japanese AAV/RPGN patients. However, maintenance treatment avoiding relapse should be established to improve renal outcomes.
    Clinical and Experimental Nephrology 02/2012; 16(4):580-8. · 1.25 Impact Factor
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    ABSTRACT: Metabolic syndrome (MS), defined as a constellation of cardiovascular disease (CVD) risk factors, is one of the fastest growing public health burdens in the Asia-Pacific region. This trend is despite the fact that people in this region are no more overweight than Europeans and Americans. Unfortunately, in South Asia, MS screening has only been performed in a few countries other than Bangladesh. Therefore the present study is designed to conduct a comprehensive screening of MS in Bangladeshi rural women, which includes estimation of prevalence and assessment of risk factor. A total of 1535 rural Bangladesh women aged ≥ 15 years were studied using a population based cross-sectional survey. The prevalence of MS was estimated using NCEP ATP III, modified NCEP ATP III and IDF criteria. The prevalence rates of MS were 25.60% (NCEP ATP III), 36.68% (modified NCEP ATP III), and 19.80% (IDF), as revealed by the present study. Furthermore, based on the NCEP ATP III criteria, 11.60% of the subjects were found to have excess waist circumference; 29.12% had elevated blood pressure, 30.42% had elevated fasting plasma glucose level, 85.47% had low HDL values and 26.91% had increased triglyceride values. Low plasma HDL level was found to be the most common abnormality in the target population and elevated waist circumference was the least frequent component. The present study reveals a high prevalence of MS and its associated risk factors in rural Bangladeshi women. These findings are important in that they provide insights that will be helpful in formulating effective public health policy, notably the development of future health prevention strategies in Bangladesh.
    BMC Public Health 01/2012; 12:49. · 2.08 Impact Factor
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    ABSTRACT: We assessed prevalence of metabolic syndrome (MS) in rural women of Bangladesh using 1485 women aged ≥15 years. The prevalence rate of MS was 31.25% (NCEP ATP III modified). And 85.05% population had low HDL values. These findings are important in the development of future health prevention strategies in Bangladesh.
    Diabetes research and clinical practice 01/2012; 95(1):e7-9. · 2.74 Impact Factor
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    ABSTRACT: Molecular mechanisms of sepsis-associated acute lung injury (ALI) are poorly defined. Since vascular endothelial growth factor (VEGF) is a potent vascular permeability and mitogenic factor, it might contribute to the development of ALI in sepsis. Thus, using lipopolysaccharide (LPS)-induced (15 mg/kg, intraperitoneal) endotoxemic rat model, we studied the timeline (1, 3, 6, and 10 h) of pulmonary VEGF expression and its signaling machinery. Levels of pulmonary VEGF and its angiogenic-mediating receptor, Flk-1, were downregulated by LPS in a time-dependent manner; levels of plasma VEGF and its permeability-mediating receptor, Flt-1, in contrast, was upregulated with time. In addition, blockade of Flt-1 could improve the downregulated pulmonary VEGF level and attenuate the elevated plasma and pulmonary levels of TNF-α, followed by improvement of arterial oxygenation and wet-to-dry weight ratio of the lung. Expression of signaling, pro- and or apoptotic factors after LPS administration were as follows: phosphorylated Akt, a downstream molecule was downregulated time dependently; endothelial nitric oxide synthase levels were significantly reduced; pro-apoptotic markers caspase 3 and Bax were upregulated whereas levels of Bcl-2 were downregulated. The present findings show that VEGF may play a role through the expression of Flt-1 in LPS-induced ALI. Moreover, downregulation of VEGF signaling cascade may account for LPS-induced apoptosis and impaired physiological angiogenesis in lung tissues, which in turn may contribute to the development of ALI induced by LPS.
    Inflammation 04/2011; 35(2):484-500. · 2.46 Impact Factor
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    ABSTRACT: Endothelin (ET)-1 is a potent vasoconstrictor that has been implicated in the pathogenesis of a number of diseases, and some studies suggest that circulating ET-1 is elevated in sepsis. The present study investigated whether ET plays a role in sepsis-mediated acute lung injury and whether its expression could be down regulated by blockade of TNF-α in septic lung. Male Wistar rats at 8 weeks of age were administered with either saline or lipopolysaccharide (LPS) at different time points (1, 3, 6 and 10 h) and various tests were then performed. The features of acute lung injury were observed at 1 h after LPS administration, which gradually became severe with time. Systolic and diastolic pressures were reduced just about one hour after LPS administration, whereas pulmonary TNF-α levels were significantly increased at various time points after LPS administration. LPS induced a time-dependent expression of ET-1 and ET(A) receptor in the lungs compared to control, peaking and increasing by 3 fold at 6 h after induction of endotoxemia, whereas levels of ET(B) receptor, which has vasodilating effects, were remarkably down regulated time-dependently. We conclude that time-dependent increase of ET-1 and ET(A) receptor with the down regulation of ET(B) receptor may play a role in the pathogenesis of acute lung injury in endotoxemia. Finally, treatment of LPS-administered rats with TNF-α blocking peptide for three hours significantly suppressed levels of pulmonary ET-1. These data taken together, led us to conclude that differential alteration in ET expression and its receptors may be mediated by TNF-α and may, in part, account for the pathogenesis of acute lung injury in endotoxemia.
    Biomedical Research 01/2011; 32(1):9-17. · 1.15 Impact Factor
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    ABSTRACT: Estrogen has widely been credited for cardioprotection in women. However, the exact mechanisms that underlie these beneficial estrogenic effects are not completely understood. Here, we sought to: 1) elucidate estrogen's influence on levels of vascular endothelial growth factor (VEGF), a key regulator of cardiovascular processes, and components of its basic signaling machinery (VEGF receptors, Akt, and eNOS) in the heart, and 2) delineate the specific estrogen receptor signaling pathway that mediates its beneficial effects using mice lacking either estrogen receptor alpha or estrogen receptor beta. We analyzed pattern of VEGF signaling and the associated coronary capillary density in the hearts of wild-type (WT), estrogen receptor alpha knockout (ERalpha-KO), and estrogen receptor beta knockout (ERbeta-KO) female mice. Deletion of estrogen receptor alpha causes a marked decrease in coronary capillary density compared to wild-type (WT) mice, while that of estrogen receptor beta had a minimal effect. Consistent with reduced coronary capillary density, cardiac expression levels of VEGF and its signaling molecules (two receptors, phosphorylated Akt, and eNOS) in ERalpha-KO mice were reduced to half of WT, in contrast to ERbeta-KO mice that only showed a slight decrease. Moreover, activity of eNOS was greatly lowered in ERalpha-KO mice. These data suggest that estrogen acts largely via estrogen receptor alpha to regulate VEGF transcription and possibly components of its basic signaling and ultimately, the development of coronary microvasculature in the heart. This molecular and histological data, in part, sheds some insights into potential mechanisms that may likely underlie estrogen's cardioprotective effects.
    European journal of pharmacology 09/2010; 641(2-3):168-78. · 2.59 Impact Factor
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    ABSTRACT: We have previously demonstrated that vascular endothelial growth factor (VEGF) is critical for cerebral angiogenesis in middle-aged female rats and may play a role in the flow-preserving neuroprotective actions of estrogen through its angiogenic and antiapoptotic properties. Here, we attempt to elucidate the effects of estrogen and the specific estrogen receptor (ER) subtype in cerebral VEGF/Akt/NO pathways and cerebral angiogenesis using 15-week old female mice that are either wild-type (WT), lack estrogen receptor α (ERαKO) or β (ERβKO). Protein levels of VEGF and basic signaling molecules of VEGF angiogenic pathway in the frontal cortex were expressed as follows, as revealed by ELISA and immunoblotting : a) VEGF; WT: ERαKO: ERβKO, 47 ± 15: 27 ± 5: 28 ± 5 pg/mg, respectively (P < 0.01); b) KDR decreased about 40% in both ERαKO and ERβKO compared to WT; c) Akt was significantly down-regulated in both ERαKO and ERβKO compared to WT; d) phosphorylated Akt (pAkt); WT: ERαKO: ERβKO, 0.6 ± 0.2: 0.3 ± 0.01: 0.3 ± 0.1 units/mg, respectively; e) phosphorylated eNOS significantly decreased about 45% in both ERαKO and ERβKO compared to WT. Cerebral capillary density decreased in both ERαKO and ERβKO compared to WT. Thus, it can be concluded that in female mice, VEGF/Akt/eNOS pathway plays an important role in cerebral angiogenesis and that both ER subtypes are involved in the regulation of VEGF and its signaling molecule expression in the frontal cortex.
    Biomedical Research 01/2010; 31(6):337-46. · 1.15 Impact Factor
  • Thrombosis Research 06/2009; 124(4):498-501. · 3.13 Impact Factor
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    ABSTRACT: Glomerular and microvascular thrombosis due to the activation of inflammation and coagulation pathway contribute to the occurrence of acute renal failure in sepsis. The protease-activated receptors (PARs) have been shown to play an important role in the interplay between inflammation and coagulation. We hypothesized that PAR-2 blocking would improve glomerular and vascular thrombosis by attenuating inflammation and coagulation, leading to the prevention of acute renal failure, and assessed the effects of the PAR-2 blocking peptide (PAR-2 BP) in a rat model of LPS-induced acute renal failure. Levels of TNF-alpha were significantly expressed 1 h after LPS administration, followed by 1) an increase in levels of tissue factor, factor VIIa, factor Xa, thrombin and plasminogen activator inhibitor 1; 2) unchanged levels of tissue factor pathway inhibitor; and 3) subsequent deposition of fibrin in kidney tissues, which led to the elevation of creatinine and blood urea nitrogen. Time-dependent PAR-2 expression was observed at both the gene and protein levels. Immunoreactivities of PAR-2 and fibrin were observed in the glomerulus and small arteries. Protease-activated receptor blocking peptide suppressed TNF-alpha elevation and attenuated activation of the coagulation, thus leading to a decrease in fibrin formation and its deposition in the glomerulus. However, the levels of creatinine and blood urea nitrogen remained unchanged. These results show that PAR-2 plays a key role in the inflammatory and coagulation process of LPS-induced renal failure; however, PAR-2 inhibition alone does not affect improvement in the renal function.
    Shock (Augusta, Ga.) 04/2009; 32(6):626-32. · 2.87 Impact Factor
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    ABSTRACT: Although endothelin-1 (ET-1) stimulates vascular endothelial growth factor (VEGF) expression in a variety of cells, including endothelial cells and vascular smooth muscle cells, the effects of ET-1 on expression of VEGF and its receptors in cardiomyocytes are unknown. In the present study, we found that treatment of neonatal rat cardiomyocytes with ET-1 for 24 h resulted in upregulation of VEGF and its two principal receptors, fetal liver kinase 1 and fms-like tyrosine kinase 1, in a concentration-dependent manner (10(-12) to 10(-6) M). ET-1 treatment also caused significant cardiomyocyte hypertrophy, as indicated by increases in cell surface area and [(14)C]leucine uptake by cardiomyocytes. Treatment with TA-0201 (10(-6) M), an ET(A)-selective blocker, eliminated ET-1-induced overexpression of VEGF and its receptors as well as cardiomyocyte hypertrophy. Treatment with VEGF neutralizing peptides (5-10 mug/ml) partially but significantly inhibited ET-1-induced cardiomyocyte hypertrophy. These results suggest that ET-1 treatment of cardiomyocytes promotes overexpression of VEGF and its receptors via activation of ET(A) receptors, and consequently the upregulated VEGF signaling system appears to contribute, at least in part, to ET-1-induced cardiomyocyte hypertrophy.
    AJP Heart and Circulatory Physiology 08/2007; 293(1):H474-81. · 4.01 Impact Factor
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    ABSTRACT: Abnormal alterations in cardiac expression of vascular endothelial growth factor (VEGF) as well as its receptors and impairment in the development of coronary collaterals have recently been reported in diabetic subjects. However, the presence of pharmacological intervention on these defects in diabetes remains unsettled. Here, we studied the effect of endothelin (ET) receptor blockade on cardiac VEGF signaling pathways and cardiac function in Sprague-Dawley rats 5 wk after induction of type I diabetes with streptozotocin (65 mg/kg ip) in comparison with age-matched control rats. After streptozotocin (1 wk), some diabetic rats were treated with the ET receptor antagonist SB-209670 (1 mg/day) for 4 wk. VEGF, its receptors, and its angiogenic signaling molecules [phosphorylated Akt and endothelial nitric-oxide synthase (eNOS)] were analyzed by Western blot, ELISA, real-time PCR, and immunohistochemistry, and cardiac function was evaluated by echocardiography. Coronary capillary morphology was assessed by lectin and enzymatic double staining. We found significant decreases in cardiac expression of VEGF, its receptors, phosphorylation of Akt and eNOS, and coronary capillary density in diabetic rats compared with controls. Treatment of diabetic rats with SB-209670 reversed these alterations to the control levels and ameliorated impairment of cardiac function. From a molecular point of view, the present study is the first to indicate the potential usefulness of an ET receptor antagonist in the treatment of cardiac dysfunction in type I diabetes.
    AJP Endocrinology and Metabolism 05/2007; 292(4):E1030-40. · 4.51 Impact Factor
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    ABSTRACT: To elucidate roles of microvascular factors in the pathogenesis of renal complications during endotoxemia, that is characterized by renal vasoconstriction and systemic hypotension/generalized non-renal vasodilation, we profile the expression pattern and time-course of three key vaso-regulators, namely endothelin (ET)-1, nitric oxide (NO), and angiotensin II (Ang II). We hypothesize that disruption of the overall balance between vasodilatation and vasoconstriction in the kidney, during the early phase of sepsis, contribute to its (kidney) predisposition to acute renal failure. Adult male Wistar rats were rendered endotoxemic at different time points (1, 3, 6 and 10 h) by a single i.p. injection of lipopolysaccharide (LPS) (15 mg/kg) dissolved in saline. Control group was injected vehicle only (saline). Both systolic and diastolic blood pressures significantly decreased at different time points after LPS administration. Surprisingly, renal histopathological evaluation showed no remarkable changes in LPS-induced endotoxemia. However, overall, levels of the vaso-regulators and, where applicable, their respective receptors were upregulated: (1) plasma ET-1 increased 25-fold and peaked, as renal ET-1 mRNA, at 3 h; renal ET-1 protein and its receptors, ET type A (ET(A)) receptor (vasoconstrictive) and ET type B (ET(B)) receptor (vasodilatatory) increased in a time-dependent fashion, (2) Ang II increased by 53% compared to control, peaking at 6 h. However, while levels of Ang II type 1 (AT1) receptor increased over time after LPS injection, those of Ang II type 2 (AT2) receptor were downregulated, (3) data of NO system (NO-NOS), the key vasodilator, were the most intriguing. Whereas levels of renal NO increased time-dependently following LPS administration, with a 2240-fold increase in renal iNOS expression, levels of eNOS, were almost unchanged. In conclusion, the present study overall reveals intriguing and complex dynamics between levels of vasoconstrictors and vasodilators during the early phase of LPS-induced endotoxemia. These shifts in molecular expressions are likely triggered by compensatory mechanisms aimed at counteracting the undesirable and dominant effects of one group of vaso-regulatory moiety over the other.
    Peptides 10/2006; 27(9):2258-70. · 2.52 Impact Factor
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    ABSTRACT: Erectile dysfunction (ED) affects approximately 50% of male patients with diabetes mellitus (DM) and is possibly due to the vascular and neuropathic complications of DM. Recently, apoptosis has been regarded as a downstream event in ED. More recently, the importance of alterations in apoptosis-related molecules in the mechanism of DM-induced ED has begun to be appreciated. Endothelin-1 (ET-1) plays a role via ET(A) and ET(B) receptors in the regulation of cavernosal smooth-muscle tone in penile tissues. We found that the ET-1 level in the penis of rats with DM was higher than that in the penis of control animals. The present study investigated a rat model in which DM was induced by a 3-week regimen of streptozotocin (STZ) to assess the expression of several apoptosis-related molecules in penile tissue and, concomitantly, the effects of ET antagonism on these changes. Male Sprague-Dawley rats (weight [+/-SD], 450 +/- 26 g) received a citrate saline vehicle or STZ (65 mg/kg ip). DM was confirmed by the presence of hyperglycemia. Diabetic animals were further separated into two treatment groups 1 week after onset of disease: one group received ET(A/B) dual receptor antagonist (SB209670) by means of osmotic minipump at a dosage of 1 mg/day, and the other group received saline. Rats in both groups were treated for 2 weeks and then sacrificed. Plasma glucose levels (+/-SD) in rats with DM were significantly higher than those in rats without DM (506 +/- 70 vs. 111 +/- 11 mg/dl). In the penile tissue of rats with DM, a 35% decrease in the expression of Bcl-2 protein (an important antiapoptotic marker detectable by immunoblotting) was seen, and ET(A/B) dual antagonist was observed to significantly counteract this decrease. Real-time polymerase chain reaction revealed that the expression of Bcl-2 mRNA was consistent with Bcl-2 protein expression. Levels of Bax and caspase-3, two important proapoptotic markers, were not significantly altered in the present study. Thus, we conclude that, in the penis of rats with early stage DM, the protection against apoptosis has decreased but can be improved by ET antagonism.
    Experimental Biology and Medicine 07/2006; 231(6):1034-9. · 2.80 Impact Factor
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    ABSTRACT: Cardiovascular complications are an important feature of diabetes mellitus (DM). Abnormal and decreased coronary collateral development has been implicated in the pathogenesis of cardiac complications in DM. More recently, decreased expression of vascular endothelial growth factor (VEGF) and its receptors has been found in diabetic heart. To our knowledge, no study has focused on the therapeutic improvement associated with VEGF in diabetic heart. DM was induced by intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats, while control rats received only citrate buffer. After 1 week, the streptozotocin-treated rats were randomly divided into two groups: one group received the selective endothelin (ET) type A receptor antagonist TA-0201 at a dose of 1 mg/kg/day for 2 weeks by osmotic mini-pump, and the vehicle group received saline only. The plasma glucose level was 504 +/- 75 mg/dl in the diabetic rats and was unchanged by treatment with ET antagonist. The body weight was decreased in the diabetic rats compared with the control rats, but the left ventricular (LV)-body weight ratio was increased in the diabetic group and was unaffected by treatment with ET antagonist. mRNA expression of VEGF and its receptors (Flt-1 and Flk-1) in the LV tissues was assessed using real-time polymerase chain reaction. VEGF expression was significantly decreased in diabetic heart and was greatly improved by treatment with ET antagonist. The expression of VEGF receptors was down-regulated in early diabetic heart but was not recovered by treatment with ET antagonist. ET and its receptor A might have differential regulation on the gene expressions of VEGF and its receptors in early diabetic heart.
    Experimental Biology and Medicine 07/2006; 231(6):902-6. · 2.80 Impact Factor

Publication Stats

423 Citations
118.21 Total Impact Points

Institutions

  • 2006–2014
    • Ibaraki Prefectural University of Health Sciences
      Ibaragi, Ōsaka, Japan
  • 1990–2014
    • University of Tsukuba
      • Institute of Clinical Medicine
      Tsukuba, Ibaraki, Japan
  • 2009
    • Hokkaido University
      • Department of Acute and Critical Care Medicine
      Sapporo-shi, Hokkaido, Japan
  • 1992
    • Shinshu University
      • Department of Pathology
      Shonai, Nagano, Japan