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Articles by H Itoh
Total Records ( 4 ) for H Itoh
  K Iskandar , Y Cao , Y Hayashi , M Nakata , E Takano , T Yada , C Zhang , W Ogawa , M Oki , S Chua , H Itoh , T Noda , M Kasuga and J. Nakae
 

Both insulin and leptin signaling converge on phosphatidylinositol 3-OH kinase [PI(3)K]/3-phosphoinositide-dependent protein kinase-1 (PDK-1)/protein kinase B (PKB, also known as Akt) in proopiomelanocortin (POMC) neurons. Forkhead box-containing protein-O1 (FoxO1) is inactivated in a PI(3)K-dependent manner. However, the interrelationship between PI(3)K/PDK-1/Akt and FoxO1, and the chronic effects of the overexpression of FoxO1 in POMC neurons on energy homeostasis has not been elucidated. To determine the extent to which PDK-1 and FoxO1 signaling in POMC neurons was responsible for energy homeostasis, we generated POMC neuron-specific Pdk1 knockout mice (POMCPdk1–/–) and mice selectively expressing a constitutively nuclear (CN)FoxO1 or transactivation-defective (256)FoxO1 in POMC neurons (CNFoxO1POMC or 256FoxO1POMC). POMCPdk1–/– mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1POMC mice exhibited mild obesity and hyperphagia compared with POMCPdk1–/– mice. Although expression of the CNFoxO1 made POMCPdk1–/– mice more obese due to excessive suppression of Pomc gene, overexpression of 256FoxO1 in POMC neurons had no effects on metabolic phenotypes and Pomc expression levels of POMCPdk1–/– mice. These data suggest a requirement for PDK-1 and FoxO1 in transcriptional regulation of Pomc and food intake.

  H Itoh , T Sakaguchi , W. G Ding , E Watanabe , I Watanabe , Y Nishio , T Makiyama , S Ohno , M Akao , Y Higashi , N Zenda , T Kubota , C Mori , K Okajima , T Haruna , A Miyamoto , M Kawamura , K Ishida , I Nagaoka , Y Oka , Y Nakazawa , T Yao , H Jo , Y Sugimoto , T Ashihara , H Hayashi , M Ito , K Imoto , H Matsuura and M. Horie
 

Background— Drugs with IKr-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown.

Methods and Results— Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS.

Conclusions— dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When IKr-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

  H Yokoyama , S Kanno , S Takahashi , D Yamada , H Itoh , K Saito , H Sone and M. Haneda
 

Background and objectives: This study investigated whether the slope of estimated GFR is different between nonproteinuric subjects with and without diabetes, and what clinical factors are associated with the GFR slope.

Design, setting, participants, & measurements: An observational cohort study was performed in 923 subjects, and the predictive value of baseline variables on the GFR slope was investigated.

Results: On the basis of the median 3-yr follow-up and 7 measurements of GFR, GFR slope (%/yr, median and interquartile range) was significantly larger in subjects with diabetes (–2.39 (–4.86 to 0.15), n = 729) than in those without diabetes (–1.02 (–4.28 to 1.37), n = 194), and this difference remained significant with or without presence of hypertension. After adjustments for confounding factors, predictors of GFR decline were found to be baseline high values of glycosylated hemoglobin A1C (HbA1C), GFR, systolic blood pressure, and low plasma total protein in subjects with diabetes, whereas only the latter two were significant in subjects without diabetes. In subjects with diabetes, the high GFR was accounted for by high HbA1C at baseline, and the predictors of GFR decline differed between those with and without hypertension, or with high and low baseline GFR. Any combination of the predictors showed increased risk for GFR decline.

Conclusions: GFR slope is substantially affected by multiple factors at various stages. The degree of chronic hyperglycemia is likely to play a crucial role in elevating GFR and accelerating the decline in patients with type 2 diabetes even from the normoalbuminuric stage.

  Y Mezaki , N Yamaguchi , K Yoshikawa , M Miura , K Imai , H Itoh and H. Senoo
 

Hepatic stellate cells (HSCs) are the major site of retinoid storage, and their activation is a key process in liver fibrogenesis. We have previously shown that expression of the retinoic acid receptor alpha (RAR) is upregulated in activated rat HSCs at a posttranscriptional level and that these RAR proteins showed a speckled distribution in the cytosol, despite their possession of a nuclear localization signal (NLS). In this report, we further characterize these cytosolic RAR proteins by using exogenously expressed RAR protein fragments or mutants tagged with a green fluorescent protein. Substitution of four amino acids, 161–164 from lysine to alanine, abolished the NLS. Exogenously expressed RAR protein fragments containing an NLS were localized exclusively in the nuclei of activated rat HSCs and never colocalized with the endogenous RAR proteins in the cytosol, suggesting that the NLS of endogenous RAR proteins is masked. Biochemical analysis showed that 65% of RAR proteins in activated HSCs were insoluble in a mixture of detergents. The insolubility of RAR proteins makes it difficult to identify RAR proteins in activated HSCs. Therefore, we propose that insoluble, speckled cytosolic distribution of RAR proteins represents a new marker of HSC activation. (J Histochem Cytochem 57:687–699, 2009)

 
 
 
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