Takashi Yoneda

Kanazawa University, Kanazawa, Ishikawa, Japan

Are you Takashi Yoneda?

Claim your profile

Publications (64)252.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: DNA methylation patterns are maintained in adult somatic cells. Recent findings, however, suggest that all methylation patterns are not preserved. We demonstrate that stimulatory signals can change the DNA methylation status at a CCAAT/enhancer binding protein (CEBP) binding site and a transcription start site and activate expression of the angiotensinogen gene (AGT). A CEBP binding site in the human AGT promoter was hypomethylated in tissues with high expression of AGT, but not in those with low expression. The transcriptional activity of AGT promoter sequences cloned into a reporter plasmid depended on DNA methylation. In cultured human cells, interleukin 6 stimulation caused DNA demethylation around a CEBP binding site and a transcription start site; demethylation was accompanied by increased CEBP-β recruitment and chromatin accessibility of the AGT promoter. DNA methylation activity decreased in the nucleus. Excess circulating aldosterone upregulated AGT expression and was accompanied by DNA hypomethylation around a CEBP binding site and a transcription start site in human visceral adipose tissue. High salt intake led to upregulation of Agt expression, DNA hypomethylation around 2 CEBP binding sites and a transcription start site, and decreased DNA methylation activity in rat visceral adipose tissue. Taken together, CEBP binding initiates chromatin relaxation and transcription, which are followed by DNA demethylation around a CEBP binding site and a transcription start site in the AGT promoter. Decreased DNA methylation activity in the nucleus may play a role in DNA demethylation. DNA demethylation switches the phenotype of AGT expression from an inactive to an active state.
    Hypertension 11/2013; 63(2). DOI:10.1161/HYPERTENSIONAHA.113.02303 · 6.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and objective: Adrenal vein sampling (AVS) is the gold standard test for identification of unilateral primary aldosteronism (PA) which is curable by surgery, but is a difficult procedure with low success rates. Rapid cortisol assays during AVS improved AVS success rates. Design and methods: We have developed a gold nanoparticles based immunochromatographic quick cortisol assay (QCA) in which cortisol concentration could be measured semi-quantitatively within 6 minutes. We evaluated the usefulness of semi-quantitative QCA at 4 centers: Kanazawa University Hospital and 3 centers with initial low AVS success rates. We randomly assigned 196 PA patients to undergo AVS using semi-quantitative QCA (semi-quantitative QCA group, n = 99) or AVS without QCA (control group, n = 97). Results: The total AVS success rate in the semi-quantitative QCA group at 4 centers was 93 of 99(94%), significantly higher than that in control group (56 of 97 (58%). Even at 3 centers with initial low AVS success rates, the AVS success rate in the semi-quantitative QCA group was 44 of 47(94%), significantly higher than that in control group (23 of 47 (49%)). Conclusions: Our new quick cortisol assay was very fast, simple, and easy and was proved to improve the AVS success rates.
    Journal of Hypertension 09/2012; 30:e191-e192. DOI:10.1097/01.hjh.0000420487.15833.ff · 4.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The activation of local renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the overall pathophysiology of the cardiorenal syndrome. We have reported increased mRNA levels of angiotensinogen, angiotensin converting enzyme (ACE) and CYP11B2 (aldosterone synthase gene) in the heart and kidney of salt-sensitive hypertensive rats complicated with cardiac hypertrophy and renal injury. However, the mechanism of control of gene expression of each component of RAAS gene in the heart and kidney is unknown. We analyzed epigenomic alteration, which controls the CYP11B2 in the human heart (cardiomyopathy, n = 9; non-cardiomyopathy, n = 6). CpG dinucleotides in the CYP11B2 promoter were found to be hypermethylated in tissues with low expression, but not in those with high expression, of CYP11B2. Methylation of the CYP11B2 promoter fused to a reporter gene decreased transcriptional activity. CYP11B2 mRNA levels were inversely correlated with CYP11B2 methylation in human myocardium, and increased CYP11B2 mRNA levels were associated with CYP11B2 demethylation in the hypertrophic heart. CpG dinucleotides in the angiotensinogen gene promoter were also found to be hypermethylated in tissues with low expression. However, no correlation between angiotenisnogen mRNA levels and methylation was found in the hypertrophic hearts. Advances in understanding of epigenetic modifications of tissue RAAS in the progression of cardiac hypertrophy and heart failure could be of great significance in predicting the pace of disease progression, developing targeted therapeutic strategies in preventing the progression of cardiorenal syndrome.
    Journal of Hypertension 09/2012; 30:e302. DOI:10.1097/01.hjh.0000420979.15610.82 · 4.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Primary aldosteronism (PA) is mainly caused by aldosterone producing adenoma and idiopathic bilateral adrenal hyperplasia (IHA). Laparoscopicadrenalectomy is recommended for the treatment of APA. Medical treatment with a mineralocorticoid receptor (MR) antagonist such as spironolactone (SP) or eplerenone(EP) is recommended for patients with IHA. Fishcher et al reported that the prevalence of spontaneous remission of IHA during long-term treatment with SP was 5.4% (Clin Endocrinol 2011). We aimed to determine the prevalence of spontaneous remission of PA during long-term treatment with MR antagonists (SP or EP) in Japan. Methods: 56 patients with PA (APA, 9 cases; IHA, 26 cases; others, 21 cases) treated with MR antagonists during more than 3 years were investigated. 36 patients were treated with SP. 20 patients were treated with EP. The patients were identified retrospectively by chart review and prospectively assessed by clinical and biochemical means. We defined complete remission (CR) of PA as normal aldosterone to renin ratio (ARR), normal suppression test, normalization of hypokalemia without hypertension. Partial remission (PR) was defined as normalization of ARR, normal suppression test, normalization of hypokalemia with hypertension. Results: The mean period of MR antagonist treatment was 4.1 years in the patients. We identified 2 (APA, 1 and IHA, 1) of 56 (3.6%) patients with CR. We also identified 8 (4 patients treated with EP; 4 patients treated with SP) (14.3%) of 56 patients with PR. Conclusions: Partial remission of PA after long-term mineralocorticoid antagonist treatment in Japan is more frequent than previously reported.
    Journal of Hypertension 09/2012; 30:e190. DOI:10.1097/01.hjh.0000420474.03264.24 · 4.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Adrenal vein sampling (AVS) after ACTH stimulation is recommended for identifying the primary aldosteronism subtypes in Japan, but the cutoff values for ascertaining lateralization of aldosterone secretion remain controversial. Methods: We examined the cutoff values of the lateralization index ((1) plasma aldosterone concentration (PAC)dominant/ plasma cortisol concentration (PCC)dominant /PACnondominant/PCCnondominant>2 before ACTH stimulation, (2) PACdominant>14000 pg/mL after ACTH stimulation, (3) PACdominant/PCCdominant/ PACnondominant/PCCnondominant>2.6, where "dominant" and "nondominant" are aldosterone or cortisol on the side with higher and lower steroid hormone secretions, respectively) in 56 patients with aldosterone-producing adenoma. Results: Thirty-two patients (57%) showed the same result according to the assessment with each criteria. The index (1) indicated 13 patients (23%) were unilateral, however, both index (2) and index (3) did not show unilateral aldosterone excess secretion. Although 8 patients (14%) were unilateral according to the index (2), both index (1) and index (3) indicated bilateral. Each index did not show the same result in 3 patients (5%). Conclusion: Further studies are necessary to know the better criteria of laterality including the usefulness of ACTH stimulation.
    Journal of Hypertension 09/2012; 30:e185. DOI:10.1097/01.hjh.0000420653.89321.93 · 4.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: High salt intake induces body weight loss in stroke-prone spontaneously hypertensive rats (SHRSP). We examined the effects of eplerenone on body weight and adipose tissue 11[beta]-hydroxysteroid dehydrogenase 1 (11[beta]-HSD1) and glucocorticoid receptor (GR) gene expression in SHRSP. Methods: Male Wistar-Kyoto (WKY) rats and SHRSP were fed a high sodium diet or normal sodium diet for 8 weeks, beginning at 5 weeks. Blood pressure, plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma corticosterone concentration (p-B) and plasma leptin levels were measured. The expression of messenger RNA (mRNA) of mineralocorticoid receptor (MR), GR, and 11[beta]-HSD1 in visceral adipose tissues were studied by real time PCR. Results: High sodium intake blunted body weight gain in SHRSP but not WKY rats. Treatment with eplerenone improved body weight in SHRSP. High sodium diet significantly increased plasma leptin levels and decreased 11[beta]-HSD1 and GR mRNA in adipose tissues of SHRSP (p<0.05). Control rats did not show any changes in these parameters by high salt intake. Treatment with eplerenone significantly decreased plasma leptin levels and increased 11[beta]-HSD1 and GR mRNA in adipose tissues of SHRSP (p<0.05). Conclusions: Eplerenone may influence leptin signals and adipose tissue glucocorticoid activity and improve body weight loss induced by high salt diet in SHRSP.
    Journal of Hypertension 09/2012; 30:e183. DOI:10.1097/01.hjh.0000420647.58827.da · 4.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Medical treatment with a mineralocorticoid receptor (MR) antagonist, which has produced spontaneous remission of bilateral primary aldosteronism (PA), may also produce spontaneous remission of unilateral PA, for which laparoscopic adrenalectomy is recommended. However, few reports exist regarding spontaneous remission after MR antagonist therapy in unilateral PA. The aim of this paper is to report a case of unilateral PA with spontaneous remission and reduction of cardiac hypertrophy after long-term spironolactone (SP) therapy. A 41-yr-old Japanese male was treated for hypertension and hypokalemia for 5 yr. Primary aldosteronism was diagnosed by a furosemide and upright posture test and a captopril challenge test. Computed tomography imaging showed a 5-mm left-sided adrenal mass. Adrenal vein sampling demonstrated overproduction of aldosterone from the left adrenal gland. Long-term treatment with SP normalized the plasma aldosterone concentration. After discontinuation of SP, the patient's blood pressure, serum potassium level, and plasma aldosterone concentration remained in the normal range. The associated cardiac hypertrophy also improved and continued to resolve even after discontinuation of SP. Although the left adrenal gland tumor was still present on computed tomography after treatment, a furosemide and upright posture test, a captopril challenge test, and a saline loading test produced no evidence of PA. Adrenal vein sampling demonstrated no sign of lateralization. These results demonstrate that SP not only antagonizes the MR, but also decreases aldosterone synthetic activity, which may produce remission in some patients with unilateral PA.
    The Journal of Clinical Endocrinology and Metabolism 02/2012; 97(4):1109-13. DOI:10.1210/jc.2011-2563 · 6.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mineralocorticoid receptor (MR) blockade is an effective treatment for hypertension and diabetic nephropathy. There are no data on the effects of MR blockade on diabetic peripheral neuropathy (DPN). The aim of this study was to determine whether MRs are present in the peripheral nerves and to investigate the effectiveness of MR blockade on DPN in streptozotocin (STZ)-induced diabetic rats. Expression of MR protein and messenger RNA (mRNA) was examined in the peripheral nerves using Western blot analysis and RT-PCR. We next studied the effects of the selective MR antagonist eplerenone and the angiotensin II receptor blocker candesartan on motor and sensory nerve conduction velocity (NCV), morphometric changes and cyclooxygenase-2 (COX-2) gene and NF-κB protein expression in the peripheral nerves of STZ-induced diabetic rats. Expression of MR protein and mRNA in peripheral nerves was equal to that in the kidney. Motor NCV was significantly improved by 8 weeks of treatment with either eplerenone (39.1 ± 1.2 m/s) or candesartan (46.4 ± 6.8 m/s) compared with control diabetic rats (33.7 ± 2.0 m/s) (p < 0.05). Sensory NCV was also improved by treatment with candesartan or eplerenone in diabetic rats. Eplerenone and candesartan caused significant improvement in mean myelin fibre area and mean myelin area compared with control diabetic rats (p < 0.05). COX-2 mRNA and NF-κB protein were significantly elevated in the peripheral nerves of diabetic rats compared with control rats, and treatment with eplerenone or candesartan reduced these changes in gene expression (p < 0.05). MR blockade may have neuroprotective effects on DPN.
    Diabetes Obesity and Metabolism 09/2011; 14(2):155-62. DOI:10.1111/j.1463-1326.2011.01499.x · 6.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: An increasing number of patients are being diagnosed with primary aldosteronism (PA) due to aldosterone-producing macroadenoma (APA). However, there are only limited data available on the clinical characteristics of PA that are associated with adrenal microadenoma. Of the 55 patients that were diagnosed with PA in our study, 22 patients showed a unilateral adrenal over-production of aldosterone. The histopathology of the surgically removed adrenal tissues led to six patients being diagnosed with microadenoma, and the clinical features of microadenoma, macroadenoma and idiopathic hyperaldosteronism (IHA) were studied. The expression levels of CYP11B2, CYP17, CYP21 and 3β-hydroxysteroid dehydrogenase 2 (HSD3B2) mRNA in the adrenal cortices (n=5 and 6, respectively) that remained attached to the adrenal microadenomas or macroadenomas were examined by real time-PCR and then compared to the expression levels in the adrenal cortices (n=5) of non-functioning adrenal adenomas (NF). The patients with microadenoma (n=6) had significantly higher diastolic blood pressure than the patients with macroadenoma (n=16) or IHA (n=33) (p<0.05). The systolic blood pressure, plasma aldosterone concentration, serum potassium level and renal function did not differ between the PA sub-groups. The levels of CYP11B2 and CYP17 mRNA were significantly increased in the adjacent tissues of microadenomas, as compared with macroadenomas or NF (p<0.05), whereas no significant differences in the CYP21 and HSD3B2 mRNA levels were found between the PA sub-groups. The tumor size did not influence the clinical characteristics of APA. The non-tumor portions of the microadenomas showed marked and sustained CYP11B2 mRNA expression under the suppressed renin-angiotensin system. We suggest that an increased number of microadenomas should be sampled, and the immunohistochemistry for steoridogenic enzymes should be investigated to clarify the etiology of microadenoma.
    Steroids 07/2011; 76(12):1363-6. DOI:10.1016/j.steroids.2011.07.004 · 2.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nuclear receptors are involved in a wide variety of functions, including aldosteronogenesis. Nuclear receptor families NR4A [nerve growth factor-induced clone B (NGFIB), Nur-related factor 1 (NURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. The present study was undertaken to elucidate the mechanism of differential regulation of nuclear receptors between cardiovascular and adrenal tissues. We collected tissues of artery (n = 9), cardiomyopathy muscle (n = 9), heart muscle (noncardiomyopathy) (n = 6), adrenal gland (n = 9) and aldosterone-producing adenoma (APA) (n = 9). 5'-rapid amplification of cDNA ends (RACE) identified transcription start sites. Multiplex reverse-transcription PCR (RT-PCR) determined use of alternative noncoding exons 1 (ANEs). In adrenocortical H295R cells, angiotensin II, KCl or cAMP, all stimulated CYP11B2 transcription and NR4A was upregulated, whereas NR2F and NR5A1 were downregulated. 5'-RACE and RT-PCR revealed four ANEs of NGFIB (NR4A1), three of NURR1 (NR4A2), two of NOR1 (NR4A3) and two of SF1 (NR5A1) in cardiovascular and adrenal tissues. Quantitative multiplex RT-PCR showed NR4A and NR5A1 differentially employed multiple ANEs in a tissue-specific manner. The use of ANEs of NGFIB and NURR1 was significantly different between APA and artery. Changes in use of ANEs of NGFIB and NOR1 were observed between cardiomyopathy and noncardiomyopathy. The NR4A mRNA levels in artery were high compared with cardiac and adrenal tissues, whereas the NR5A1 mRNA level in adrenal tissues was extremely high compared with cardiovascular tissues. NR4A and NR5A1 genes are complex in terms of alternative promoter use. The use of ANEs may be associated with the pathophysiology of the heart and adrenal gland.
    Journal of Hypertension 06/2011; 29(6):1185-95. DOI:10.1097/HJH.0b013e32834626bb · 4.72 Impact Factor
  • Source
    Yoshiyu Takeda · Shigehoro Karashima · Takashi Yoneda
    [Show abstract] [Hide abstract]
    ABSTRACT: Primary aldosteronism (PA) has been recognized as a common cause of secondary hypertension and accounts for approximately 5-15% of the hypertensive population in Japan. Screening for PA should therefore be carried out in all hypertensive patients as we have shown the estimated prevalence of PA is 13.6% in pre-hypertensive subjects and 9.1% in stage 1 hypertensive patients. The screening test most advocated is the aldosterone-to-renin ratio (ARR), and when the ARR is >20 the following confirmatory tests should be carried out; the captopril challenge test, frusemide-upright test, or saline infusion test. Adrenal CT is not accurate for distinguishing between an aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Adrenal venous sampling (AVS) is therefore essential for selecting the appropriate therapy in patients a high probability of PA who require surgical treatment. Rapid cortisol assays during AVS to monitor cortisol levels can reduce the failure associated with AVS. We have developed a new rapid cortisol assay using immunochromatography, in which cortisol concentration can be measured within 6 min. Using this technique, the success rate of AVS improved to 93%. IHA underlies about one-half of cases with PA; treatment with eplerenone (100 mg twice a daily), a specific mineralocorticoid receptor antagonist, results in substantial improvement in hypertension, with fewer side effects compared to spironolactone.
    Reviews in Endocrine and Metabolic Disorders 03/2011; 12(1):21-5. DOI:10.1007/s11154-011-9164-6 · 4.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have reported a high prevalence of primary aldosteronism among patients with severe hypertension. However, the prevalence of this disease among normotensive and mildly hypertensive patients has not been determined. The aim of this study was to examine the prevalence of primary aldosteronism among prehypertensive and stage 1 hypertensive subjects. A total of 292 adult subjects with hypertension or prehypertension was screened for primary aldosteronism. Subjects with a plasma aldosterone concentration (ng per 100 ml) to plasma renin activity (ng ml(-1) h(-1)) ratio (ARR) above 20 underwent confirmatory captopril suppression testing. A total of 54 subjects (18.5%) had an ARR above 20. A captopril suppression test was performed in 17 of 54 subjects with probable primary aldosteronism. The test confirmed the diagnosis of primary aldosteronism in 11 (64.7%) of 17 patients, giving a least prevalence of 3.8% for this disease. The 11 patients with primary aldosteronism had a mean ± s.d. systolic blood pressure of 139 ± 4 mm Hg, diastolic blood pressure of 95 ± 10 mm Hg and serum potassium of 4.46 ± 0.48 mEq l(-1) at the time of screening test. The prevalence of primary aldosteronism as could be assessed in this study was at least 6.8% in prehypertensive patients, 3.3% in stage 1 hypertensive patients and 3.1% in stage 2 hypertensive patients. In conclusion, this study suggests a high prevalence of primary aldosteronism among prehypertensive and stage 1 hypertensive Japanese patients. Significant numbers of prehypertensive individuals may have subclinical forms of this disease.
    Hypertension Research 10/2010; 34(1):98-102. DOI:10.1038/hr.2010.166 · 2.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The combination of a pituitary prolactinoma and an aldosterone-producing adrenal adenoma is extremely rare. To the best of our knowledge, double endocrine tumors in association with heart-hand syndrome have not previously been reported. A 21-year-old Japanese woman presented with galactorrhea and decreased visual acuity. A large pituitary adenoma with an increased level of serum prolactin was apparent by computed tomography. She additionally showed mild hypertension (136/90 mmHg) accompanied by hypokalemia. The plasma aldosterone concentration was increased. Computed tomography showed a mass in the right adrenal gland. No other tumors were found despite extensive imaging studies. Physical and radiographic examinations showed skeletal malformations of the hands and feet, including hypoplasia of the first digit in all four limbs. An atrial septal defect was demonstrated by echocardiography. Similar digital and cardiac abnormalities were detected in our patient's father, and a clinical diagnosis of hereditary heart-hand syndrome was made. No established heart-hand syndrome was wholly compatible with the family's phenotype. Her father had no obvious endocrine tumors, implying that the parent of transmission determined variable phenotypic expression of the disease: heart-hand syndrome with multiple endocrine tumors from the paternal transmission or no endocrine tumor from the maternal transmission. This suggests that the gene or genes responsible for the disease may be under tissue-specific imprinting control.
    Journal of Medical Case Reports 10/2010; 4:347. DOI:10.1186/1752-1947-4-347
  • [Show abstract] [Hide abstract]
    ABSTRACT: Elevation of serum parathyroid hormone (PTH) in patients with medullary thyroid cancer (MTC) is usually found in multiple endocrine neoplasia type 2A (MEN2A). However, ectopic production of PTH is rare and its molecular etiology remains largely uninvestigated. We report a case of ectopic production of PTH by a sporadic MTC. The etiology of ectopic PTH gene expression was examined, focusing on GCM2 which has a crucial role in developing parathyroid glands. We observed ectopic expression of the PTH and GCM2 genes in tissues from the tumor and metastatic lymph nodes. However, GCM2 gene expression was also detected in adjacent thyroid tissue and lymphoblasts, in which PTH gene expression was absent. Hypomethylation of the PTH promoter, which is reportedly associated with ectopic production of PTH, was not seen in either the tumor tissue or metastatic lymph nodes. Meanwhile, DNA hypomethylation was seen in a CpG island identified in the GCM2 promoter region, regardless of whether or not the GCM2 gene was expressed. We showed that transcriptional activity of the CpG island sequences cloned into a reporter plasmid was dependent upon DNA methylation. Finally, we present the first report of a PTH-producing MTC. There was no apparent association between ectopic PTH and GCM2 gene expression, despite co-expression of the two genes. Neither genomic rearrangement nor DNA hypomethylation in the PTH gene appeared responsible for ectopic production of PTH. Although DNA hypomethylation may be necessary for the GCM2 gene expression, ectopic expression of GCM2 won't be possible by DNA hypomethylation alone.
    Endocrine Journal 12/2009; 57(2):161-70. DOI:10.1507/endocrj.K09E-131 · 2.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: High-salt diets decrease insulin sensitivity in salt-sensitive hypertensive rats, and glucocorticoids promote adipocyte growth and may have pathophysiological roles in the metabolic syndrome. The aim of this study was to clarify the relationship between high-salt diet and the adipocyte glucocorticoid hormones in salt-sensitive hypertensive rats. Six-week-old Dahl salt-sensitive (DS) hypertensive rats and salt-resistant (DR) rats were fed a high-salt diet or a normal-salt diet for 4 weeks. Fasting blood glucose (FBG), serum adiponectin, plasma insulin, and corticosterone in plasma and in visceral adipose tissues, 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) activities in adipose tissues and glucose uptake in isolated muscle were measured. Animals underwent an oral glucose tolerance test (OGTT). The expression of mRNA for glucocorticoid receptor (GR), 11beta-HSD1 and tumor necrosis factor-alpha (TNF-alpha) in adipose tissues were measured using a real-time PCR. A high-salt diet did not influence FBG; however, decreased 2-deoxy glucose uptake and plasma insulin during OGTT in DS rats. The high-salt diet increased significantly adipose tissue corticosterone concentration and 11beta-HSD1 activities, gene expression for GR, 11beta-HSD1 and TNF-alpha in adipose tissues in DS rats compared with DR rats (p<0.05). The high-salt diet did not influence plasma corticosterone and serum adiponectin concentration in DS and DR rats. These results suggest that changes in GR and 11beta-HSD1 in adipose tissue may contribute to insulin sensitivity in salt-sensitive hypertensive rats.
    Steroids 07/2009; 74(12):978-82. DOI:10.1016/j.steroids.2009.07.006 · 2.64 Impact Factor
  • CVD Prevention and Control 05/2009; 4. DOI:10.1016/S1875-4570(09)60568-4
  • Yoshiyu Takeda · Aoshuang Zhu · Takashi Yoneda
    CVD Prevention and Control 05/2009; 4. DOI:10.1016/S1875-4570(09)60044-9
  • [Show abstract] [Hide abstract]
    ABSTRACT: The (pro)renin receptor exists in the kidney, blood vessels and the heart. (Pro)renin binds to the receptor and induces tissue injuries directly, completely independent of angiotensin II (Ang II). The renal renin-angiotensin-aldosterone system is activated in salt-sensitive hypertensive rats with in-vitro studies showing aldosterone increases angiotensin-converting enzyme (ACE) activity, renin production and angiotensin II type 1 receptor (AT1R) activity. However, the effect of blockade of mineralocorticoid receptor on the renal (pro)renin receptor, angiotensinogen, ACE and AT1R in Dahl salt-sensitive rats is unknown. The following parameters were measured in Dahl salt-sensitive rats and in Dahl salt-resistant rats fed high-salt or low-salt diets and treated for 8 weeks with or without eplerenone (100 mg/kg per day, orally): blood pressure, plasma renin activity, plasma aldosterone concentration, kidney weight and Ang II contents, urinary protein excretion, glomerular injury (assessed by semiquantitative morphometric analysis) and levels of expression in the kidney of (pro)renin receptor protein and messenger RNA (mRNA) for angiotensinogen, ACE and AT1R. Dahl salt-sensitive rats fed a high-salt diet had increased kidney/body weight (175%) and urinary protein excretion (886%) and decreased plasma renin activity and plasma aldosterone concentration. The rats developed progressive sclerotic and proliferative glomerular changes, concomitant with increased expression of renal (pro)renin receptor protein and mRNA levels of angiotensinogen, ACE and AT1R and kidney Ang II content. Treatment with eplerenone in Dahl salt-sensitive rats was associated with significant improvements in kidney to body weight ratio, urinary protein excretion and renal injury scores and decreased renal (pro)renin receptor protein expression and angiotensinogen and AT1R mRNA levels and kidney Ang II content. A high salt diet increased the renal renin-angiotensin system, whereas blockade of mineralocorticoid receptors attenuated renal injuries by decreasing the activity of tissue renin-angiotensin system in Dahl salt-sensitive rats.
    Journal of Hypertension 05/2009; 27(4):800-5. DOI:10.1097/HJH.0b013e328325d861 · 4.72 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aldosterone is an important pathogenetic factor, independent of the renin-angiotensin system in cardiovascular and renal disease. Aldosterone breakthrough during angiotensin-converting enzyme (ACE) inhibitor therapy was reported in hypertension, diabetes mellitus, and chronic renal disease. It is unclear whether the angiotensin II receptor blocker (ARB) causes aldosterone breakthrough in patients with hypertension and diabetes mellitus, and whether aldosterone breakthrough contributes to renal injury in these patients. We prospectively studied 95 hypertensive patients with diabetes mellitus. Patients were treated with candesartan (8 mg/day, n = 47) or valsartan (80 mg/day, n = 48) for 15 months. Blood pressure (BP), urinary albumin excretion (UAE), biochemical markers, plasma aldosterone concentration (PAC), and plasma renin activity (PRA) were measured before and at 3, 6, 12, and 15 months of treatment. Nine patients who exhibited aldosterone breakthrough after treatment with ARB were placed on spironolactone (25 mg/day) for 3 months, and BP, UAE, and biochemical markers were measured after treatment. Although the overall PAC was significantly decreased (P < .05) in each group, it eventually increased in 21 (candesartan, 11 patients; valsartan, 10 patients) of 95 patients (22%; aldosterone breakthrough). Blood pressure, PRA, and biomedical markers did not differ between the two groups during treatment. Although UAE was significantly decreased in patients with or without aldosterone breakthrough at 6 months, it was increased again at 15 months of treatment in patients with aldosterone breakthrough. Treatment with spironolactone markedly reduced UAE in these patients. Aldosterone breakthrough was seen to be equal in hypertensive patients with diabetes mellitus treated with candesartan or valsartan. Aldosterone blockade therapy may be effective in preventing renal injury in hypertensive patients with aldosterone breakthrough.
    American Journal of Hypertension 12/2007; 20(12):1329-33. DOI:10.1016/j.amjhyper.2007.09.001 · 2.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We previously reported that a high-sodium diet activates the local renin-angiotensin-aldosterone system (RAAS) in cardiovascular tissues of Dahl salt-sensitive hypertensive (DS) rats. Angiotensin-converting enzyme 2 (ACE2) is a novel regulator of blood pressure (BP) and cardiac function. The effect of blockade of aldosterone or angiotensin II (Ang II) on cardiac angiotensinogen and ACE2 in DS rats is unknown. The BP, plasma renin activity (PRA), plasma aldosterone concentration (PAC), heart weight, endothelium-dependent relaxation (EDR), and messenger RNA (mRNA) levels of collagen III, angiotensinogen, ACE, and ACE2 in the heart were measured in DS rats and in Dahl salt-resistant (DR) rats fed high or low salt diets. The rats were treated orally with or without eplerenone (100 mg/kg/d), candesartan (10 mg/kg/d), or both drugs combined for 8 weeks. A high salt diet increased BP (140%), heart/body weight (132%), and collagen III mRNA levels (146%) and decreased PRA and PAC concomitant with increased expression of cardiac angiotensinogen mRNA and decreased mRNA levels of ACE2 in DS rats. Eplerenone or candesartan significantly decreased the systolic BP from 240 +/- 5 mm Hg to 164 +/- 4 mm Hg or to 172 +/- 10 mm Hg, respectively (P < .05). Eplerenone or candesartan partially improved heart/body weight and cardiac fibrosis, improved EDR and decreased cardiac ACE and angiotensinogen mRNA levels in DS rats. Candesartan increased ACE2 mRNA levels in the heart. Combination therapy normalized BP and further improved cardiac hypertrophy, fibrosis, and EDR. In DS rats, blockade of aldosterone or Ang II protects cardiac hypertrophy and fibrosis by inactivation of the local RAAS in the heart.
    American Journal of Hypertension 11/2007; 20(10):1119-24. DOI:10.1016/j.amjhyper.2007.05.008 · 2.85 Impact Factor

Publication Stats

1k Citations
252.80 Total Impact Points


  • 1991–2013
    • Kanazawa University
      • • Department of Internal Medicine
      • • Graduate School of Medical Sciences
      • • Department of Cardiovascular Medicine
      • • School of Medicine
      Kanazawa, Ishikawa, Japan
  • 1996–2005
    • Kanazawa Medical University
      • Department of Internal Medicine (III)
      Kanazawa, Ishikawa, Japan