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Papers - Ito, Hiroshi

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Usefulness of C-reactive protein to high-molecular-weight adiponectin ratio to predict insulin resistance and metabolic syndrome in Japanese men

Saisho, Y., Hirose, H., Seino, Y., Saito, I. and Itoh, H.

J Atheroscler Thromb 17 ( 9 ) 944 - 52 2010.09

ISSN 1340-3478

AIM: We questioned whether the ratio of C-reactive protein to high-molecular-weight adiponectin (C/A ratio), compared to each value alone, is more useful to predict insulin resistance and/or metabolic syndrome. METHODS: We measured serum CRP and HMW adiponectin levels in 841 Japanese men who had participated in an annual health checkup. Correlations of the C/A ratio with metabolic parameters were assessed, and its predictive values for insulin resistance and MetS were compared with CRP or HMW adiponectin alone. RESULTS: The C/A ratio was higher in subjects with MetS (n = 114) than in those without MetS (0.46 +/- 0.67 vs. 0.23 +/- 0.39, p<0.0001). The C/A ratio was correlated with a larger number of metabolic parameters than CRP, but the correlation was comparable to HMW adiponectin. Likewise, the area under the curve of the C/A ratio in receiver operator characteristic analysis for MetS was greater than that of CRP, but comparable to that of HMW adiponectin. However, the AUC of the C/A ratio in ROC analysis for insulin resistance (HOMA-IR >2.5) was greater than that of CRP or HMW adiponectin alone. CONCLUSION: While the C/A ratio provided little advantage to predict MetS, it might be more useful to predict insulin resistance than CRP or HMW adiponectin alone.

Sirt1 plays an important role in mediating greater functionality of human ES/iPS-derived vascular endothelial cells

Homma, K., Sone, M., Taura, D., Yamahara, K., Suzuki, Y., Takahashi, K., Sonoyama, T., Inuzuka, M., Fukunaga, Y., Tamura, N., Itoh, H., Yamanaka, S. and Nakao, K.

Atherosclerosis 212 ( 1 ) 42 - 7 2010.09

ISSN 0021-9150

OBJECTIVE: We previously succeeded in inducing and isolating vascular endothelial cells (ECs) from both human embryonic stem (ES) and induced pluripotent stem (iPS) cells. Here, we compared the functionality of human adult ECs (HAECs), human ES-derived ECs (ESECs) and human iPS-derived ECs (iPSECs). METHODS AND RESULTS: We compared the cell proliferative potential, potential for migration, and tolerance to oxidative stress. ESECs were significantly superior to HAECs in all of these cell functions. The cell functions of iPSECs were comparable to those of ESECSs and also superior to HAECs. We then analyzed the gene expressions of HAECs, ESECs and iPSECs, and observed that the expression level of Sirt1, a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, is higher in ESECs and iPSECs than in HAECs. The inhibition of Sirt1 with a Sirt1-specific inhibitor and siRNA antagonized these differences between the three types of cells. CONCLUSIONS: Sirt1 plays a key role in the high cellular function of ESECs and iPSECs. Although further in vivo investigations are required, this study initially demonstrated the potential of ESECs and iPSECs as the cell source for regenerative medicine, and also showed the potential of ES cells as a useful tool for elucidating the molecular mechanism of cell aging.

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Blood pressure-independent effect of candesartan on cardio-ankle vascular index in hypertensive patients with metabolic syndrome

Bokuda, K., Ichihara, A., Sakoda, M., Mito, A., Kinouchi, K. and Itoh, H.

Vasc Health Risk Manag 6 571 - 8 2010.08

ISSN 1176-6344

Angiotensin receptor blockers (ARBs) are known to reduce the cardiovascular risk in hypertensive patients. This study was designed to examine the effect of an ARB candesartan on subclinical atherosclerosis assessed by cardio-ankle vascular index (CAVI) in comparison with calcium channel blockers (CCBs) alone in hypertensive patients with metabolic syndrome (MetS). A total of 53 consecutive hypertensive patients with MetS were randomly assigned to the candesartan group, in which candesartan was added on, or the CCBs group, in which CCBs were added on. Clinical and biological parameters were obtained before and after the 12-month treatment period. The primary measure of efficacy was the %change in CAVI. When treated with candesartan, but not CCBs, CAVI significantly decreased from 8.7 to 7.7 by 11%. Blood pressure (BP) significantly decreased with both treatments, but the differences between groups were not significant. The changes in other parameters remained unchanged in both the groups. Analysis of covariance found that both the BP reduction and the therapy difference contributed to the decrease in CAVI, but the BP reduction was not involved in the decrease in CAVI caused by the difference in the therapy. Candesartan may be a better antihypertensive drug than CCBs to improve subclinical atherosclerosis of patients with MetS.

The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes

Kinouchi, K., Ichihara, A., Sano, M., Sun-Wada, G. H., Wada, Y., Kurauchi-Mito, A., Bokuda, K., Narita, T., Oshima, Y., Sakoda, M., Tamai, Y., Sato, H., Fukuda, K. and Itoh, H.

Circ Res 107 ( 1 ) 30 - 4 2010.07

ISSN 0009-7330

RATIONALE: The (pro)renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H(+)-ATPase (V-ATPase), implicating a non-RAS-related function of ATP6AP2. OBJECTIVE: We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes. METHODS AND RESULTS: Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the V(O) subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes. CONCLUSIONS: Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non-RAS-related function that is essential for cell survival.

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Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2

Hayashi, K., Sasamura, H., Ishiguro, K., Sakamaki, Y., Azegami, T. and Itoh, H.

Kidney Int 78 ( 1 ) 69 - 78 2010.07

ISSN 0085-2538

Understanding mechanisms that contribute to the regression of glomerulosclerosis is important for developing new strategies to treat chronic kidney disease. We reported that transient high-dose treatment with an angiotensin receptor blocker causes regression of renal arteriolar hypertrophy and hypertension in spontaneously hypertensive rats. To extend those findings to another form of kidney disease, we examined the short- and long-term effects of transient high-dose angiotensin receptor blocker treatment in a mouse model of adriamycin-induced glomerulosclerosis. A 2-week course of candesartan caused a dose-dependent regression of established glomerulosclerotic lesions sustained for over 6 months following cessation of treatment. Highly sensitive in situ zymography and activity assays showed that glomerular matrix metalloproteinase (MMP)-2 activity was increased after high-dose angiotensin blocker therapy. Treatment of cultured podocytes with candesartan resulted in an increase in MMP-2 activity. The regression of glomerulosclerosis was partially attenuated in mice pretreated with the MMP inhibitor doxycycline, as well as in MMP-2 knockout mice. Our results suggest that transient high-dose angiotensin receptor blocker treatment effectively induced sustained regression of glomerulosclerosis by a mechanism mediated, in part, by changes in MMP-2 activity.

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Add-on blockade of (pro)renin receptor in imidapril-treated diabetic SHRsp

Seki, Y., Ichihara, A., Mizuguchi, Y., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Bokuda, K. and Itoh, H.

Front Biosci (Elite Ed) 2 972 - 9 2010.06

ISSN 1945-0494

To examine the involvement of (pro)renin receptor in the accelerated organ damage in streptozotocin-induced diabetic male SHRsp, the rats fed a high-salt diet were divided into 5 groups: a group treated with the vehicle, a group treated with 15 mg/kg/day of imidapril (ACEi), a group treated with 60 mg/kg/day of imidapril (High ACEi), a group treated with handle region peptide (HRP), and a group treated with both ACEi and HRP (ACEi+HRP). After 8 weeks, the arterial pressure was similar in the vehicle and HRP groups and decreased in the ACEi-treated groups. The renal angiotensin II content decreased similarly in the groups treated with ACEi and/or HRP. Urinary protein excretion also decreased in the ACEi, High ACEi, and HRP groups and significantly further decreased in the ACEi+HRP group. The heart weight of the ACEi+HRP group was significantly lower than that of any other groups, although the cardiac angiotensin II levels decreased similarly in the groups treated with ACEi and/or HRP. Thus, (pro)renin receptor contributes to the accelerated pathogenesis in the heart and kidneys of diabetic SHRsp.

Pancreatic beta-cell function and fetal growth in gestational impaired glucose tolerance

Miyakoshi, K., Tanaka, M., Saisho, Y., Shimada, A., Minegishi, K., Kim, S. H., Asai, S., Itoh, H. and Yoshimura, Y.

Acta Obstet Gynecol Scand 89 ( 6 ) 769 - 75 2010.06

ISSN 0001-6349

OBJECTIVE: To investigate the metabolic phenotype and pregnancy outcomes of gestational impaired glucose tolerance (IGT) defined by isolated hyperglycemia during an oral glucose tolerance test (OGTT). DESIGN: Retrospective cohort study. SETTING: University referral hospital. POPULATION: A total of 4,789 women were screened for gestational diabetes mellitus (GDM) between 1996 and 2008 with a glucose challenge test (GCT), followed by a 2-hour 75-g OGTT if the GCT result was abnormal; in addition, measurement of plasma insulin concentration during the OGTT was implemented from 2004. METHODS: The insulin sensitivity (IS(OGTT)) and beta-cell function (insulinogenic index/homeostasis model assessment for insulin resistance) were calculated for 283 women who underwent a diagnostic OGTT between 2004 and 2008. Perinatal complications were examined in 4,789 women who were screened for GDM between 1996 and 2008. MAIN OUTCOME MEASURES: Comparison of outcomes among women stratified by glucose tolerance status using the GCT and OGTT profiles. RESULTS: Insulin sensitivity and beta-cell function significantly decreased from normal OGTT to 2-hour IGT (single hyperglycemia at 2 hours) to 1-hour IGT (single hyperglycemia at 1 hour) to GDM, with significant differences between normal OGTT and 1-hour IGT or GDM. The occurrence of large-for-gestational age (LGA) neonates was significantly increased in women with GDM or 1-hour IGT (adjusted odds ratio: 2.15, 2.22; 95% confidence interval 1.23-3.75 and 1.04-4.35, respectively) compared to those with normal GCT or normal diagnostic OGTT results. CONCLUSIONS: Like GDM, isolated 1-hour hyperglycemia on the OGTT is associated with beta-cell dysfunction and an increased risk for LGA neonates.

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Renoprotective effects of mineralocorticoid receptor blockade in heminephrectomized (pro)renin receptor transgenic rats

Mizuguchi, Y., Ichihara, A., Seki, Y., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Bokuda, K. and Itoh, H.

Clin Exp Pharmacol Physiol 37 ( 5-6 ) 569 - 73 2010.05

ISSN 0305-1870

1. Nephropathy and elevated plasma aldosterone concentrations (PAC) have been observed in (pro)renin receptor transgenic (TG) rats. In the present study, we hypothesized that PAC and/or mineralocorticoid receptor contribute to the nephropathy of TG rats. To test this hypothesis, the effects of a high-sodium (8% NaCl) diet and heminephrectomy on PAC were examined. 2. Feeding of the high-sodium diet for 12 weeks similarly decreased PAC in TG and wild-type (WT) rats. Heminephrectomy further reduced PAC in TG rats fed a high-sodium diet, but had no effect on PAC in WT rats fed a high-sodium diet. 3. Next, the effects of eplerenone (125 mg/kg per day) and dietary salt restriction (0.36% NaCl diet) on proteinuria and renal morphology were examined in rats fed a high-sodium diet or subjected to heminephrectomy. Both eplerenone and dietary sodium restriction significantly reduced the arterial pressure of TG rats, but had no effect in WT rats. In TG rats, treatment with eplerenone significantly decreased urinary protein excretion, but dietary sodium restriction did not. 4. Nephrin and podocin mRNA levels, as determined by real-time quantitative reverse transcription-polymerase chain reaction, were significantly lower in TG rats than in WT rats. In TG rats, eplerenone treatment significantly increased nephrin mRNA levels, but not podocin mRNA levels. Dietary salt restriction significantly increased mRNA levels of both nephrin and podocin. Although zonula occludens (ZO)-1 mRNA levels were similar in both WT and TG rats, eplerenone treatment significantly decreased ZO-1 mRNA levels in TG rats. 5. The results of the present study suggest that the improvement in proteinuria following eplerenone treatment is independent of its effects on sodium balance and may be mediated by effects on the expression of slit diaphragm proteins.

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Aliskiren inhibits intracellular angiotensin II levels without affecting (pro)renin receptor signals in human podocytes

Sakoda, M., Ichihara, A., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Murohashi-Bokuda, K., Saleem, M. A., Nishiyama, A., Suzuki, F. and Itoh, H.

Am J Hypertens 23 ( 5 ) 575 - 80 2010.05

ISSN 0895-7061

BACKGROUND: A direct renin inhibitor (DRI) had a benefit in decreasing albuminuria in type 2 diabetic patients having already been treated with angiotensin (Ang) II type 1 receptor blocker (ARB), suggesting that aliskiren may have another effect other than blockade of the traditional renin-angiotensin system (RAS). Recently, prorenin bound to (pro)renin receptor ((P)RR) was found and shown to evoke two pathways; the generation of Ang peptides and the receptor-dependent activation of extracellular signal-related protein kinase (ERK). Because (P)RR is present in the podocytes, a central component of the glomerular filtration barrier, we hypothesized that aliskiren influences the (P)RR-induced two pathways in human podocytes. METHODS: Human podocytes were treated with 2 nmol/l prorenin in the presence and absence of an angiotensin-converting enzyme inhibitor (ACEi) imidaprilat, an ARB candesartan, a DRI aliskiren, or the siRNA knocking down the (P)RR mRNA and the intracellular AngII levels and the phosphorylation of ERK were determined. RESULTS: The expression of (P)RR mRNA of human podocytes was unaffected by the treatment with RAS inhibitors, but decreased by 69% with the siRNA treatment. The basal levels of intracellular AngII and the prorenin-induced increase in intracellular AngII were significantly reduced by aliskiren and siRNA treatment, compared with imidaprilat and candesartan. The prorenin-induced ERK activation was reduced to control level by the siRNA treatment, but it was unaffected by imidaprilat, candesartan, or aliskiren. CONCLUSIONS: Aliskiren is the most potent inhibitor of intracellular AngII levels of human podocytes among RAS inhibitors, although it is incapable of inhibiting the (P)RR-dependent ERK phosphorylation.

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Adrenocortical zonation in humans under normal and pathological conditions

Nishimoto, K., Nakagawa, K., Li, D., Kosaka, T., Oya, M., Mikami, S., Shibata, H., Itoh, H., Mitani, F., Yamazaki, T., Ogishima, T., Suematsu, M. and Mukai, K.

J Clin Endocrinol Metab 95 ( 5 ) 2296 - 305 2010.05

ISSN 0021-972

CONTEXT: Aldosterone synthase (CYP11B2) and steroid 11 beta-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiation of human adrenocortical cells. Little is known, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions. OBJECTIVE: The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other. RESULTS: Under normal conditions, CYP11B2 was sporadically detected in the zona glomerulosa, whereas CYP11B1 was entirely detected in the zonae fasciculata-reticularis. Adrenocortical cells lacking both enzymes were observed in the outer cortical regions. In addition to conventional zonation, we found a variegated zonation consisting of a subcapsular cell cluster expressing CYP11B2, which we termed aldosterone-producing cell cluster, and a CYP11B1-expressing area. Aldosterone-producing adenomas differed in cell populations expressing CYP11B2 from one another, whereas CYP11B1-expressing and double-negative cells were also intermingled. Adenomas from patients with Cushing's syndrome expressed CYP11B1 entirely but not CYP11B2, resulting in atrophic nontumor glands. The nontumor portions of both types of adenomas bore frequently one or more aldosterone-producing cell clusters, which sustained CYP11B2 expression markedly under the conditions of the suppressed renin-angiotensin system. CONCLUSION: Immunohistochemistry of the human normal adrenal cortex for CYP11B2 and CYP11B1 revealed a variegated zonation with cell clusters constitutively expressing CYP11B2. This technique may provide a pathological confirmatory diagnosis of adrenocortical adenomas.

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Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function

Hasegawa, K., Wakino, S., Yoshioka, K., Tatematsu, S., Hara, Y., Minakuchi, H., Sueyasu, K., Washida, N., Tokuyama, H., Tzukerman, M., Skorecki, K., Hayashi, K. and Itoh, H.

J Biol Chem 285 ( 17 ) 13045 - 56 2010.04

ISSN 0021-9258

Sirt1, a NAD-dependent protein deacetylase, is reported to regulate intracellular metabolism and attenuate reactive oxidative species (ROS)-induced apoptosis leading to longevity and acute stress resistance. We created transgenic (TG) mice with kidney-specific overexpression of Sirt1 using the promoter sodium-phosphate cotransporter IIa (Npt2) driven specifically in proximal tubules and investigated the kidney-specific role of Sirt1 in the protection against acute kidney injury (AKI). We also elucidated the role of number or function of peroxisome and mitochondria in mediating the mechanisms for renal protective effects of Sirt1 in AKI. Cisplatin-induced AKI decreased the number and function of peroxisomes as well as mitochondria and led to increased local levels of ROS production and renal tubular apoptotic cells. TG mice treated with cisplatin mitigated AKI, local ROS, and renal tubular apoptotic tubular cells. Consistent with these results, TG mice treated with cisplatin also exhibited recovery of peroxisome number and function, as well as rescued mitochondrial function; however, mitochondrial number was not recovered. Immunoelectron microscopic findings consistently demonstrated that the decrease in peroxisome number by cisplatin in wild type mice was restored in transgenic mice. In HK-2 cells, a cultured proximal tubule cell line, overexpression of Sirt1 rescued the cisplatin-induced cell apoptosis through the restoration of peroxisome number, although the mitochondria number was not restored. These results indicate that Sirt1 overexpression in proximal tubules rescues cisplatin-induced AKI by maintaining peroxisomes number and function, concomitant up-regulation of catalase, and elimination of renal ROS levels. Renal Sirt1 can be a potential therapeutic target for the treatment of AKI.

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NF-YC functions as a corepressor of agonist-bound mineralocorticoid receptor

Murai-Takeda, A., Shibata, H., Kurihara, I., Kobayashi, S., Yokota, K., Suda, N., Mitsuishi, Y., Jo, R., Kitagawa, H., Kato, S., Saruta, T. and Itoh, H.

J Biol Chem 285 ( 11 ) 8084 - 93 2010.03

ISSN 0021-9258

The role of aldosterone has been implicated in the metabolic syndrome and cardiovascular diseases. The biological actions of aldosterone are mediated through mineralocorticoid receptor (MR). Nuclear receptor-mediated gene expression is regulated by dynamic and coordinated recruitment of coactivators and corepressors. To identify new coregulators of the MR, full-length MR was used as bait in yeast two-hybrid screening. We isolated NF-YC, one of the subunits of heterotrimeric transcription factor NF-Y. Specific interaction between MR and NF-YC was confirmed by yeast two-hybrid, mammalian two-hybrid, coimmunoprecipitation assays, and fluorescence subcellular imaging. Transient transfection experiments in COS-7 cells demonstrated that NF-YC repressed MR transactivation in a hormone-sensitive manner. Moreover, reduction of NF-YC protein levels by small interfering RNA potentiated hormonal activation of endogenous target genes in stably MR-expressing cells, indicating that NF-YC functions as an agonist-dependent MR corepressor. The corepressor function of NF-YC is selective for MR, because overexpression of NF-YC did not affect transcriptional activity mediated by androgen, progesterone, or glucocorticoid receptors. Chromatin immunoprecipitation experiments showed that endogenous MR and steroid receptor coactivator-1 were recruited to an endogenous ENaC gene promoter in a largely aldosterone-dependent manner, and endogenous NF-YC was sequentially recruited to the same element. Immunohistochemistry showed that endogenous MR and NF-YC were colocalized within the mouse kidney. Although aldosterone induces interaction of the N and C termini of MR, NF-YC inhibited the N/C interaction. These findings indicate that NF-YC functions as a new corepressor of agonist-bound MR via alteration of aldosterone-induced MR conformation.

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Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Murohashi-Bokuda, K. and Itoh, H.

Hypertens Res 33 ( 3 ) 177 - 80 2010.03

ISSN 0916-9636

Numerous in vitro and in vivo animal studies using the (pro)renin receptor (P)RR blocker handle region peptide have suggested an important role of (P)RR in the pathogenesis of end-stage organ damage in patients with diabetes and hypertension. In addition, a limited number of clinical studies have suggested an association between (P)RR gene polymorphisms and blood pressure levels and between (P)RR mRNA levels and angiotensin-converting enzyme mRNA levels in human arteries. However, recent studies have shown that the (P)RR is divided into its soluble form and a residual hydrophobic part, which includes ATPase 6 associated protein 2, within cells. Therefore, the (P)RR may have a more complex function than previously thought. In addition, the physiological roles of the (P)RR remain undetermined, because the construction of (P)RR null mice has not been successful. As a next step for research in this area, a method for determining the soluble (P)RR levels in plasma and urine and the construction of tissue-specific (P)RR-knockout mice are needed to elucidate the roles of the (P)RR in physiology and pathophysiology.

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Brachial-ankle pulse wave velocity predicts silent cerebrovascular diseases in patients with end-stage renal diseases

Washida, N., Wakino, S., Hayashi, K., Kuwahara, T. and Itoh, H.

J Atheroscler Thromb 17 ( 2 ) 165 - 72 2010.02

ISSN 1340-3478

AIM: Cerebrovascular disease (CVD) is a major determinant of the prognosis in end-stage renal diseases (ESRD). The purpose of this study was to examine whether factors associated with arterial stiffness contributed to the development of CVD in patients with ESRD. METHODS: CVD (lacunes and carotid/intracranial artery stenosis) was evaluated with brain magnetic resonance imaging (MRI), and carotid/intracranial artery magnetic resonance angiography (MRA) in 44 pre-dialytic patients. The severity of CVD was evaluated by the number of lacunes and the degree of stenosis, respectively. The association between CVD and atherosclerotic parameters was evaluated. RESULTS: Patients with severe lacunes (n=18) manifested older age, lower diastolic blood pressure, serum creatinine and albumin, and higher CRP and serum calcium than those with absent-moderate lacunes (n=26). When assessed by multivariate analysis, only baPWV was adopted as an independent risk factor for severe lacunes. Furthermore, baPWV and i-PTH were associated with the severity of carotid/intracranial artery stenosis, both of which were independent of other risk factors, including age and diabetes. CONCLUSIONS: Arterial stiffness may constitute a novel determinant predicting the severity of CVD in pre-dialytic patients besides classical risk factors.

[Anti-atherosclerotic effects by PPARgamma and its ligands through the activation of reverse cholesterol transport system]

Wakino, S. and Itoh, H.

Nihon Rinsho 68 ( 2 ) 217 - 23 2010.02

ISSN 0047-1852

Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a nuclear receptor superfamily which agonists were in clinical use for anti-diabetic therapy. Recent studies both in vivo and in vitro revealed that PPARgamma agonists have anti-atherosclerotic effects which is also demonstrated by a large clinical trial including PROactive study. One of the mechanisms for this effect is the activation of reverse cholesterol transport through the induction of ABCA1 transporter by PPARgamma agonists. The transporter exports cholesterol from macrophages migrating in the vasculature and inhibits the formation of foam cell which contains lipid droplet in the cytosol as cholesterol ester. Clinical application of PPARgamma agonists have beneficial effects by preventing the cardiovascular events in diabetic patients.

Absence of gelatinase (MMP-9) or collagenase (MMP-13) attenuates adriamycin-induced albuminuria and glomerulosclerosis

Sakamaki, Y., Sasamura, H., Hayashi, K., Ishiguro, K., Takaishi, H., Okada, Y., D'Armiento, J. M., Saruta, T. and Itoh, H.

Nephron Exp Nephrol 115 ( 2 ) e22 - 32 2010

ISSN 1660-2129

BACKGROUND/AIMS: The role of matrix metalloproteinases (MMPs) in the pathogenesis of glomerular injury appears to be complex. To investigate the role of individual MMPs, we examined the course of Adriamycin-induced albuminuria and glomerulosclerosis in mice lacking either a gelatinase (MMP-9) or a collagenase (MMP-13). METHODS: Adriamycin was administered to MMP-9 or MMP-13 knockout (KO) mice. Glomerular injury was assessed by the quantification of albuminuria, the glomerular injury score and type IV collagen immunostaining. RESULTS: Treatment of mice with Adriamycin (18 mg/kg i.v.) resulted in marked albuminuria and glomerulosclerosis reaching a peak at 4-8 weeks. The albuminuria and glomerulosclerosis were significantly (p < 0.05) attenuated in both the MMP-9 KO and MMP-13 KO mice compared to controls. In contrast, treatment of wild-type mice with the broad-spectrum MMP inhibitor doxycycline did not have a beneficial effect on the albuminuria and glomerulosclerosis. CONCLUSION: These results support a role for both gelatinase (MMP-9) and collagenase (MMP-13) in the pathogenesis of glomerular injury in the Adriamycin-induced glomerulosclerosis model. MMP inhibitors with high specificity towards MMP-9 and/or MMP-13 may be potential future candidates to provide more effective therapies to inhibit the development of glomerulosclerosis.

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Beta cell dysfunction and its clinical significance in gestational diabetes

Saisho, Y., Miyakoshi, K., Tanaka, M., Shimada, A., Ikenoue, S., Kadohira, I., Yoshimura, Y. and Itoh, H.

Endocr J 57 ( 11 ) 973 - 80 2010

ISSN 0918-8959

The aim of this study is to explore beta cell dysfunction and its clinical significance in gestational diabetes mellitus (GDM). We assessed insulin sensitivity and insulin secretion in a total of 277 Japanese women between 24 and 27 weeks of pregnancy who underwent a 2 h, 75 g oral glucose tolerance test (OGTT) because of an abnormal result on a 1 h 50 g oral glucose challenge conducted as part of a standard screening for GDM. Insulin sensitivity was evaluated by an insulin sensitivity index derived from OGTT (IS(OGTT)), whereas insulin secretion was calculated as a ratio of the total area under the insulin curve to the total area under the glucose curve (AUC(ins/glu)). Beta cell function in relation to insulin sensitivity (i.e. disposition index) was derived from the product of insulin sensitivity and insulin secretion (i.e. AUC(ins/glu) x IS(OGTT)). In women diagnosed with GDM (n=57), the disposition index was significantly lower than that in those without GDM, irrespective of obesity. The disposition index in women with GDM was significantly correlated with levels of fasting and mean preprandial capillary glucose and HbA1c before initiating insulin therapy (r = -0.45, -0.38, -0.49, respectively). Furthermore, there was a significant correlation between the disposition index and total insulin dosage to achieve glycemic goal (r = -0.41). In conclusion, we demonstrated beta cell dysfunction in Japanese women with GDM irrespective of obesity. The level of beta cell dysfunction in GDM was associated with the severity of glucose intolerance and total insulin dosage required. These findings underpin clinical significance of beta cell dysfunction in GDM.

CXC chemokine ligand 10 DNA vaccination plus Complete Freund's Adjuvant reverses hyperglycemia in non-obese diabetic mice

Oikawa, Y., Shimada, A., Yamada, Y., Okubo, Y., Katsuki, T., Shigihara, T., Miyazaki, J., Narumi, S. and Itoh, H.

Rev Diabet Stud 7 ( 3 ) 209 - 24 2010

ISSN 1613-6071

OBJECTIVE: Complete Freund's Adjuvant (CFA) is known to arrest autoimmune diabetes development in non-obese diabetic (NOD) mice. However, CFA alone cannot induce effective remission in diabetic NOD mice. Previously, we reported that anti-CXC chemokine ligand 10 (CXCL10) antibody can promote beta-cell proliferation in NOD mice. In the present study, we aimed to examine whether anti-CXCL10 plus CFA treatment can effectively reverse autoimmune diabetes development. METHODS: Systemic supply of anti-CXCL10 antibody by CXCL10 DNA vaccination in combination with CFA injection was performed in new-onset diabetic NOD mice. Remission rate of diabetes, histological characteristics of residual insulitis lesions, residual beta-cell mass, and regulatory T cell population in local pancreas were examined. RESULTS: A high frequency of diabetes reversal was observed after combination treatment with anti-CXCL10 plus CFA. In mice showing diabetes reversal, residual beta-cell mass was significantly increased, and some beta-cells were in a proliferative state. Although systemic cytokine profiles were unaffected, the frequency of "hybrid regulatory T cells", i.e. regulatory T cells expressing CXCR3, was significantly increased in local pancreatic lesions. This was possibly associated with the regulation of anti-islet autoimmunity. CONCLUSIONS: Anti-CXCL10 plus appropriate immune adjuvant therapy arrested, and reversed, type 1 diabetes development.

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Effects of telmisartan on arterial stiffness assessed by the cardio-ankle vascular index in hypertensive patients

Kinouchi, K., Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Murohashi-Bokuda, K. and Itoh, H.

Kidney Blood Press Res 33 ( 4 ) 304 - 12 2010

ISSN 1420-4096

BACKGROUND/AIMS: This study was conducted to determine the effect of telmisartan on the cardio-ankle vascular index (CAVI), a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients. METHODS: One hundred consecutive hypertensive patients were randomly assigned either to a group treated with calcium channel blocker (CCB)-based therapy or a group treated with telmisartan-based therapy. Clinical and biological parameters were then measured before and 12 months after the start of this study. RESULTS: CAVI, the logarithm of urinary albumin excretion, and BP were reduced significantly after telmisartan-based therapy. The decreases in 24-hour diastolic BP and daytime systolic BP associated with telmisartan-based therapy were significantly greater than those associated with CCB-based therapy. Both therapies significantly and similarly decreased the clinical BP, 24-hour systolic BP, daytime diastolic BP and serum levels of low-density lipoprotein cholesterol. No significant differences in the metabolic parameters were observed between the two therapies. CONCLUSION: Telmisartan-based therapy had beneficial effects on arterial stiffness assessed by CAVI, albuminuria, 24-hour BP and metabolism compared with CCB-based therapy. Since these markers are known to influence the future risk of cardiovascular events, telmisartan could be a useful drug for hypertensive patients.

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New approaches to blockade of the renin-angiotensin-aldosterone system: characteristics and usefulness of the direct renin inhibitor aliskiren

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Bokuda, K. and Itoh, H.

J Pharmacol Sci 113 ( 4 ) 296 - 300 2010

ISSN 1347-8613

Since renin inhibition interferes with the first and rate-limiting steps in the renin-angiotensin system, the renin step is a very attractive target for lowering blood pressure and minimizing target-organ damage. The newly developed direct renin inhibitor aliskiren has several attractive characteristics: it definitively reduces plasma renin activity among inhibitors of the renin-angiotensin system, is remarkably specific for human renin, exhibits a long half-life in plasma comparable to that of amlodipine, and has a high affinity for renal glomeruli and vasculature. Although these characteristics suggest the clinical usefulness and safety of aliskiren, several problems remain unsolved. Why does aliskiren have beneficial effects on the heart and kidneys of patients treated with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1-receptor blockers (ARBs)? Is the blood-pressure-lowering effect of aliskiren dependent on the plasma renin activity? Does aliskiren exert a possible adverse effect via (pro)renin receptor-dependent intracellular signals? Here, we review the characteristics and usefulness of aliskiren and discuss the current issues associated with this direct renin inhibitor.

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