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Papers - Ito, Hiroshi

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Coactivation of SF-1-mediated transcription of steroidogenic enzymes by Ubc9 and PIAS1

Suda, N., Shibata, H., Kurihara, I., Ikeda, Y., Kobayashi, S., Yokota, K., Murai-Takeda, A., Nakagawa, K., Oya, M., Murai, M., Rainey, W. E., Saruta, T. and Itoh, H.

Endocrinology 152 ( 6 ) 2266 - 77 2011.06

ISSN 0013-7227

Steroidogenic factor-1 (SF-1) is a nuclear orphan receptor, which is essential for adrenal development and regulation of steroidogenic enzyme expression. SF-1 is posttranslationally modified by small ubiquitin-related modifier-1 (SUMO-1), thus mostly resulting in attenuation of transcription. We investigated the role of sumoylation enzymes, Ubc9 and protein inhibitors of activated STAT1 (PIAS1), in SF-1-mediated transcription of steroidogenic enzyme genes in the adrenal cortex. Coimmunoprecipitation assays showed that both Ubc9 and PIAS1 interacted with SF-1. Transient transfection assays in adrenocortical H295R cells showed Ubc9 and PIAS1 potentiated SF-1-mediated transactivation of reporter constructs containing human CYP17, CYP11A1, and CYP11B1 but not CYP11B2 promoters. Reduction of endogenous Ubc9 and PIAS1 by introducing corresponding small interfering RNA significantly reduced endogenous CYP17, CYP11A1, and CYP11B1 mRNA levels, indicating that they normally function as coactivators of SF-1. Wild type and sumoylation-inactive mutants of Ubc9 and PIAS1 can similarly enhance the SF-1-mediated transactivation of the CYP17 gene, indicating that the coactivation potency of Ubc9 and PIAS1 is independent of sumoylation activity. Chromatin immunoprecipitation assays demonstrated that SF-1, Ubc9, and PIAS1 were recruited to an endogenous CYP17 gene promoter in the context of chromatin in vivo. Immunohistochemistry and Western blotting showed that SF-1, Ubc9, and PIAS1 were expressed in the nuclei of the human adrenal cortex. In cortisol-producing adenomas, the expression pattern of SF-1 and Ubc9 were markedly increased, whereas that of PIAS1 was decreased compared with adjacent normal adrenals. These results showed the physiological roles of Ubc9 and PIAS1 as SF-1 coactivators beyond sumoylation enzymes in adrenocortical steroidogenesis and suggested their possible pathophysiological roles in human cortisol-producing adenomas.

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Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice

Maki, T., Ihara, M., Fujita, Y., Nambu, T., Miyashita, K., Yamada, M., Washida, K., Nishio, K., Ito, H., Harada, H., Yokoi, H., Arai, H., Itoh, H., Nakao, K., Takahashi, R. and Tomimoto, H.

Stroke 42 ( 4 ) 1122 - 8 2011.04

ISSN 0039-2499

BACKGROUND AND PURPOSE: Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia. METHODS: A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. RESULTS: After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM. CONCLUSIONS: These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.

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Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

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

Hypertens Res 34 ( 3 ) 301 - 7 2011.03

ISSN 0916-9636

The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-beta mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-beta mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.

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[Antihypertensive therapy in the patient with diabetes mellitus or metabolic syndrome]

Miyashita, K. and Itoh, H.

Nihon Naika Gakkai Zasshi 100 ( 2 ) 376 - 84 2011.02

ISSN 0021-5384

Rho and Rho-kinase activity in adipocytes contributes to a vicious cycle in obesity that may involve mechanical stretch

Hara, Y., Wakino, S., Tanabe, Y., Saito, M., Tokuyama, H., Washida, N., Tatematsu, S., Yoshioka, K., Homma, K., Hasegawa, K., Minakuchi, H., Fujimura, K., Hosoya, K., Hayashi, K., Nakayama, K. and Itoh, H.

Sci Signal 4 ( 157 ) ra3 2011.01

ISSN 1945-0877

The development of obesity involves multiple mechanisms. Here, we identify adipocyte signaling through the guanosine triphosphatase Rho and its effector Rho-kinase as one such mechanism. Mice fed a high-fat diet (HFD) showed increased Rho-kinase activity in adipose tissue compared to mice fed a low-fat diet. Treatment with the Rho-kinase inhibitor fasudil attenuated weight gain and insulin resistance in mice on a HFD. Transgenic mice overexpressing an adipocyte-specific, dominant-negative form of RhoA (DN-RhoA TG mice) showed decreased Rho-kinase activity in adipocytes, decreased HFD-induced weight gain, and improved glucose metabolism compared to wild-type littermates. Furthermore, compared to HFD-fed wild-type littermates, DN-RhoA TG mice on a HFD showed decreased adipocyte hypertrophy, reduced macrophage recruitment to adipose tissue, and lower expression of mRNAs encoding various adipocytokines. Lipid accumulation in cultured adipocytes was associated with increased Rho-kinase activity and increased abundance of adipocytokine transcripts, which was reversed by a Rho-kinase inhibitor. Direct application of mechanical stretch to mature adipocytes increased Rho-kinase activity and stress fiber formation. Stress fiber formation, which was also observed in adipocytes from HFD-fed mice, was prevented by Rho-kinase inhibition and in DN-RhoA TG mice. Our findings indicate that lipid accumulation in adipocytes activates Rho to Rho-kinase (Rho-Rho-kinase) signaling at least in part through mechanical stretch and implicate Rho-Rho-kinase signaling in inflammatory changes in adipose tissue in obesity. Thus, inhibition of Rho-Rho-kinase signaling may provide a therapeutic strategy for disrupting a vicious cycle of adipocyte stretch, Rho-Rho-kinase signaling, and inflammation of adipose tissue that contributes to and aggravates obesity.

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[The cutting-edge of medicine; metabolic domino and CKD]

Itoh, H.

Nihon Naika Gakkai Zasshi 100 ( 1 ) 191 - 8 2011.01

ISSN 0021-5384

Podocytes as a target of prorenin in diabetes

Sakoda, M., Itoh, H. and Ichihara, A.

Curr Diabetes Rev 7 ( 1 ) 17 - 21 2011.01

ISSN 1573-3998

High plasma prorenin levels predict the onset of microvascular complications, such as albuminuria/proteinuria,in diabetic patients. In diabetic rats with elevated plasma prorenin levels, treatment with HRP, which competitively inhibits the binding of prorenin to the (pro)renin receptor [(P)RR] as a decoy peptide, significantly prevented the development of albuminuria/proteinuria and glomerulosclerosis, suggesting that (P)RR-bound prorenin plays a significant role in the pathogenesis of diabetic nephropathy. Recently, the presence of (P)RR in podocytes, which represent one of the glomerular filtration barriers, has been reported. Although podocytes are subjected to both high glucose levels and mechanical stretching caused by glomerular hyperfiltration under diabetic conditions, the expression of (P)RR is reportedly regulated by high glucose levels in in vitro mesangial cells and the in vivo kidneys of diabetic rats, whereas mechanical stretching is up-regulated by (P)RR expression in human podocytes. In addition, prorenin treatment not only leads to the generation of intracellular angiotensin (Ang)II, but also activates the phosphorylation of ERK via (P)RR in a manner that acts independently of AngII in human podocytes. Thus, the upregulation of prorenin and (P)RR in podocytes as a result of glomerular hyperfiltration might play an important role in the development of albuminuria/proteinuria via the generation of intracellular AngII and the stimulation of (P)RR-dependent intracellular signals. Further inquiry regarding podocyte (P)RR intracellular signal transduction will be needed to develop a new therapeutic approach targeting podocyte (P)RR in patients with diabetic nephropathy.

[Mitochondrial dysfunction in metabolic syndrome]

Wakino, S. and Itoh, H.

Nihon Rinsho 69 Suppl 1 26 - 31 2011.01

ISSN 0047-1852

[Hypertension and arteriosclerosis]

Sasamura, H. and Itoh, H.

Nihon Rinsho 69 ( 1 ) 125 - 30 2011.01

ISSN 0047-1852

Hypertension is a known risk factor for arteriosclerosis, and causes both atherosclero= sis of medium-large arteries and arteriolosclerosis of the arterioles. Elevated blood pressure causes damage to the endothelium and vascular wall through both mechanical and humoral factors. We and others have shown that inhibition of the renin-angiotensin system at a 'critical period' during the development of hypertension results in a permanent suppression of hypertension in animal models. We have also reported that high-dose renin-angiotensin inhibition results in regression of hypertension, possibly by regression of renal arteriolar hypertrophy. These results suggest that understanding the process of arterial remodeling may play a key role in the development of new strategies for prevention and regression of hypertension and arteriosclerosis.

Proatherogenic effect of interleukin-18 is exerted with high-fat diet, but not with normal diet in spontaneously hyperlipidemic mice

Imai, T., Oikawa, Y., Shimada, A., Oguchi, S., Takamiya, Y., Katsuki, T., Okubo, Y., Osaki, T., Tahara, H., Matsushima, Y., Miyazaki, J. and Itoh, H.

J Atheroscler Thromb 18 ( 12 ) 1090 - 101 2011

ISSN 1340-3478

AIM: It has been considered that interleukin (IL)-18, a T helper 1(Th1) type cytokine, has a promoting effect on atherosclerosis development. A previous mouse study demonstrated that short-term exogenous IL-18 promoted atherosclerosis through a Th1 type immune response; however, the serum IL-18 may have increased greatly beyond its physiological range, and the effect of increased serum IL-18 on atherosclerosis development has not been investigated under different conditions of dietary fat content. The purpose of this study was to reveal the effect of increased serum IL-18 within its physiological fluctuations on atherosclerosis development under different conditions of dietary fat content. METHODS: Spontaneously hyperlipidemic (SHL) mice were systemically supplied with IL-18 for 10 weeks by means of an in vivo gene transfer system with a high-fat diet containing 0.15% cholesterol or a normal diet. RESULTS: Serum IL-18 steadily elevated within its physiological fluctuations. An atherosclerotic lesion area in the aortic root significantly increased with a high-fat diet. Systemic cytokine balance shifted to a Th1-dominant state, and IL-12 mRNA in the arterial wall significantly increased with a high-fat diet; however, these findings were not observed with a normal diet. CONCLUSIONS: It was suggested that the proatherogenic effect of IL-18 is physiologically exerted exclusively with a high-fat diet through Th1 type immune responses, but not with a normal diet.

A case of membranous nephropathy with primary biliary cirrhosis and cyclosporine-induced remission

Sakamaki, Y., Hayashi, M., Wakino, S., Fukuda, S., Konishi, K., Hashiguchi, A., Hayashi, K. and Itoh, H.

Intern Med 50 ( 3 ) 233 - 8 2011

ISSN 0918-2918

We report a case of membranous nephropathy with primary biliary cirrhosis (PBC). A 76-year-old Japanese man had been treated for PBC and was referred to our department because of acute severe proteinuria (10 g/day). Renal biopsy was performed and was compatible with a diagnosis of membranous nephropathy. The patient was treated with cyclosporine A (CsA; Neoral(R)), which was followed by normalization of liver function and partial remission of proteinuria (0.68 g/day) within six months without any significant side effects. This case suggests that CsA monotherapy is effective for the treatment of both liver dysfunction and membranous nephropathy associated with PBC.

Postprandial serum C-peptide to plasma glucose ratio as a predictor of subsequent insulin treatment in patients with type 2 diabetes

Saisho, Y., Kou, K., Tanaka, K., Abe, T., Kurosawa, H., Shimada, A., Meguro, S., Kawai, T. and Itoh, H.

Endocr J 58 ( 4 ) 315 - 22 2011

ISSN 0918-8959

Type 2 diabetes is a progressive disease and most patients with type 2 diabetes eventually need insulin therapy. The objective of this study was to clarify C-peptide immunoreactivity (CPR), a marker of beta cell function, as a predictor of requirement for insulin therapy. We conducted a retrospective study of 579 consecutive subjects with type 2 diabetes who were admitted to our hospital from 2000 to 2007 and were able to be followed up for at least 6 months after discharge. Fasting and postprandial serum CPR and urinary CPR levels had been measured during admission. Information about insulin therapy at the last visit was obtained from medical records. At the last visit, 364 subjects (62.9%) were treated with insulin. Mean interval between discharge and the last visit was 4.5 +/- 2.3 years. Serum and urine CPR levels at baseline were significantly associated with insulin treatment at the last visit (P<0.001 for all). Among CPR values, postprandial serum CPR to plasma glucose ratio (CPR index) showed the greatest area under the receiver operating characteristic (ROC) curve for insulin therapy. Multivariate logistic regression analysis evaluating the effect of postprandial CPR index adjusted for other confounders showed consistent results with unadjusted results. In conclusion, beta cell dysfunction is significantly correlated with future insulin therapy in patients with type 2 diabetes. Our study indicates that among CPR measurements, postprandial CPR index is the best predictive marker for future insulin therapy.

Prediction of recovery time from hypoglycemia in patients with insulin overdose

Ohyama, T., Saisho, Y., Muraki, A., Kawai, T. and Itoh, H.

Endocr J 58 ( 7 ) 607 - 11 2011

ISSN 0918-8959

Insulin overdose results in prolonged hypoglycemia. We hypothesized that if a huge amount of insulin is subcutaneously injected, the duration of hypoglycemia depends on the dose of insulin rather than the type of insulin. We conducted a literature review of insulin overdose and 33 cases were included in this study. We assessed the correlation between recovery time from hypoglycemia and insulin dose. As a result, there was a significant correlation between recovery time from hypoglycemia and insulin dose (r=0.88, p<0.0001) and this correlation was expressed as y=0.045x; where y is time (h) and x is insulin dose (U), corresponding to that if 1000 U insulin is injected, hypoglycemia will persist for ~45 h. This equation may be useful to predict the duration of glucose supplementation for treatment of insulin overdose.

Plasma 25-hydroxyvitamin d is independently associated with hemoglobin concentration in male subjects with type 2 diabetes mellitus

Meguro, S., Tomita, M., Katsuki, T., Kato, K., Oh, H., Ainai, A., Ito, R., Takeda, S., Kawai, T., Atsumi, Y., Itoh, H. and Hasegawa, H.

Int J Endocrinol 2011 362981 2011

ISSN 1687-8337

Introduction. It was reported that 25-hydroxyvitamin D level was independently associated with anemia in chronic kidney diseases, but the relation between vitamin D and anemia in diabetes mellitus is not still certain. We analyzed the relation between plasma 25-hydroxyvitamin D level and hemoglobin concentration. Materials and Methods. A cross-sectional study in male patients with type 2 diabetes was performed. Correlation coefficients and standardized partial regression coefficient for the hemoglobin concentration were evaluated. Results. Hemoglobin concentration was positively correlated with body mass index, HbA1c, estimated glomerular filtration rate, cholinesterase, and 25-hydroxyvitamin D level and negatively correlated with age, duration of diabetes mellitus, serum creatinine, and urinary albumin creatinine ratio. Multiple regression analysis revealed the independent relation of 25-hydroxyvitamin D to hemoglobin concentration. Conclusions. Plasma circulating form of vitamin D is significantly associated with hemoglobin concentration in diabetes mellitus independent of the clinical markers for kidney function or nutrition.

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Free cortisol/cortisone ratio in pooled urine was increased after rapid-ACTH stimulation test under dexamethasone suppression

Koyama, Y., Homma, K., Murata, M., Shibata, H., Itoh, H. and Hasegawa, T.

Endocr J 58 ( 12 ) 1099 - 103 2011

ISSN 0918-8959

We employ rapid-ACTH stimulation test under dexamethasone (DEX) suppression to assess the adrenal function in daily clinic. However, we have little knowledge about the excretion of urinary free cortisol (FF) and cortisone (FE) in pooled urine in this setting. The purpose was to examine the changes of FF and FE as well as FF/FE ratio in pooled urine after rapid-ACTH stimulation test under DEX suppression using stable isotope dilution-gas chromatography/mass spectrometry (SID-GC/MS). Pooled urine samples were collected from 8 patients (age 33-71 years) who were suspected to have primary aldsteronism. They all were finally diagnosed as having normal glucocorticoid secretion. We performed rapid-ACTH stimulation test with DEX suppression for consecutive 4 days as follows. (1) 24 hour urine samples were serially collected from 2300 h on day 1 for 72 hours (Basal, DEX1mg, and DEX8mg-ACTH). (2) 1 and 8 mg DEX was given at 2300 h on day 2 and 3, respectively. (3) 250 microg of ACTH was given at 0900 h on day 4. Urine free steroids were delivered with bismethylenedioxy-heptafluorobutyric anhydride and analyzed by SID-GC/MS (microg/day). From DEX1mg to DXE8mg-ACTH, (1) FF and FE were significantly increased (3.9+/-1.3 to 21.3+/-14.6 and 12.4+/-4.8 to 26.1+/-11.0 microg/day, respectively), but (2) FF/FE ratio significantly increased (0.32+/-0.05 to 0.77+/-0.23). These data suggested that newly synthesized cortisol by ACTH stimulation was not efficiently metabolized to cortisone.

Differential Effects in Cardiovascular Markers between High-Dose Angiotensin II Receptor Blocker Monotherapy and Combination Therapy of ARB with Calcium Channel Blocker in Hypertension (DEAR Trial)

Kinouchi, K., Ichihara, A., Bokuda, K., Kurosawa, H. and Itoh, H.

Int J Hypertens 2011 284823 2011

Background/Aims. Arterial stiffness is an independent risk factor for cardiovascular morbidity and mortality. This study was conducted to determine the effect of olmesartan (OLM) and azelnidipine (AZL) on arterial stiffness using the cardio-ankle vascular index (CAVI), which is a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients. Methods. Fifty-two consecutive hypertensive patients were randomly assigned either to a group treated with OLM monotherapy or to a group treated with OLM and AZL combination therapy. Clinical and biological parameters were measured before and 12 months after the start of this study. Results. Both therapies significantly and similarly reduced BP, augmentation index, and plasma aldosterone levels. The combination therapy significantly decreased CAVI and serum low-density lipoprotein (LDL-C) levels and these reductions were significantly greater than those produced with monotherapy. No significant differences in metabolic parameters were observed between the two therapies. Conclusion. The combination therapy with OLM and AZL had beneficial effects on arterial stiffness assessed by CAVI, LDL-C, and metabolism, despite the similar BP reduction, compared with OLM monotherapy. Since these markers are known to influence the future risk of cardiovascular events, combination therapy with OLM and AZL could be a useful choice for treating hypertensive patients.

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Effects of olmesartan medoxomil, an angiotensin II type 1 receptor antagonist, on plasma concentration of B-type natriuretic peptide, in hypertensive patients with type 2 diabetes mellitus: a preliminary, observational, open-label study

Kawai, T., Takei, I., Shimada, A., Hirata, T., Tanaka, K., Saisho, Y., Irie, J., Horimai, C., Matsumoto, H. and Itoh, H.

Clin Drug Investig 31 ( 4 ) 237 - 45 2011

ISSN 1173-2563

BACKGROUND AND OBJECTIVE: Angiotensin II type 1 (AT1) receptor antagonists (angiotensin receptor blockers [ARBs]) are widely used for the treatment of not only hypertension but also cardiac dysfunction. B-type natriuretic peptide (BNP) is secreted mainly by the cardiac ventricle and plays an important role in the regulation of blood pressure (BP) and body fluid. It has been established that the plasma level of BNP is increased in patients with chronic heart failure in proportion to the severity of cardiac dysfunction. Because cardiac dysfunction is closely associated with a high risk of mortality in patients with diabetes mellitus, early identification and prevention of cardiac dysfunction are important. The objective of this study was to determine the effects of olmesartan medoxomil, a novel ARB, on the plasma level of BNP in hypertensive patients with type 2 diabetes. METHODS: This was a preliminary, prospective, observational, open-label study. Sixty-eight type 2 diabetic patients with hypertension (systolic BP [SBP]>/=140 mmHg or diastolic BP [DBP]>/=90 mmHg) received olmesartan medoxomil 10-20 mg/day for 24 weeks. Plasma levels of BNP, as well as several clinical parameters of glycaemic control and lipid metabolism, were compared before and after 24 weeks of treatment. Another group consisting of 22 age- and body mass index-matched subjects not treated with olmesartan medoxomil was observed for reference purposes. RESULTS: In the olmesartan medoxomil group, mean+/-SD SBP decreased from 152.8+/-16.4 at baseline to 146.8+/-14.4 mmHg after 24 weeks' treatment (p<0.05); similarly, mean+/-SD DBP decreased from 85.6+/-10.5 to 81.3+/-11.6 mmHg (p<0.05). In 53 subjects in whom plasma levels of BNP could be measured both before and after treatment, mean+/-SD BNP decreased from 41.3+/-49.9 to 32.5+/-36.3 pg/mL (p<0.05). Change in plasma BNP level over the 24-week treatment period in the olmesartan medoxomil group was not correlated with change in SBP or DBP. Multiple regression analysis revealed that change in plasma BNP level was not correlated with baseline value of or change in any other parameters. No other parameters in the olmesartan medoxomil group, and no parameters in the non-olmesartan medoxomil reference group, showed significant changes. CONCLUSION: The current preliminary study showed that olmesartan medoxomil treatment might decrease plasma BNP levels, independent of its BP-lowering effect, in hypertensive patients with type 2 diabetes.

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Tumor necrosis factor-alpha converting enzyme inactivation ameliorates high-fat diet-induced insulin resistance and altered energy homeostasis

Kaneko, H., Anzai, T., Horiuchi, K., Morimoto, K., Anzai, A., Nagai, T., Sugano, Y., Maekawa, Y., Itoh, H., Yoshikawa, T., Okada, Y., Ogawa, S. and Fukuda, K.

Circ J 75 ( 10 ) 2482 - 90 2011

ISSN 1346-9843

BACKGROUND: Tumor necrosis factor (TNF)-alpha, which is released as a soluble form by ectodomain shedding of TNF-alpha converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study. METHODS AND RESULTS: Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-alpha expression in liver, and increased adipocyte size, macrophage infiltration and TNF-alpha and monocyte chemoattractant protein-1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1. CONCLUSIONS: Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders.

Effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy in patients with type 2 diabetes, in relation to suppression of N(varepsilon)-carboxymethyl lysine

Kawai, T., Takei, I., Tokui, M., Funae, O., Miyamoto, K., Tabata, M., Hirata, T., Saruta, T., Shimada, A. and Itoh, H.

J Diabetes Complications 24 ( 6 ) 424 - 32 2010.11

ISSN 1056-8727

OBJECTIVE: We investigated the efficacy of epalrestat, an aldose reductase inhibitor, for diabetic peripheral neuropathy in Japanese patients with type 2 diabetes. METHODS: A total of 38 type 2 diabetic patients (22 men and 16 women; mean +/- S.E.M. age 63.3 +/- 1.0 years; duration of diabetes 9.6 +/- 0.8 years) with diabetic neuropathy were newly administered 150 mg/day epalrestat (EP group). Motor nerve conduction velocity (MCV), sensory nerve conduction velocity (SCV), and minimum F-wave latency were evaluated before administration of epalrestat and after 1 and 2 years. Serum N(varepsilon)-carboxymethyl lysine (CML) as a parameter of advanced glycation end products (AGEs), lipid peroxide, and soluble vascular cell adhesion molecule (sVCAM)-1 as a parameter of angiopathy were measured before administration and after 1 year. We compared the results with those of 36 duration of diabetes-matched type 2 diabetic patients (mean +/- S.E.M. duration of diabetes 8.2 +/- 0.7 years) as control (C group). RESULTS: The EP group showed significant suppression of deterioration of MCV (P<.01) and minimum F-wave latency (P<.01) in the tibial nerve and SCV (P<.05) in the sural nerve compared to those in the C group after 2 years. There was a significant difference in change in CML level between groups (-0.18 +/- 0.13 mU/ml in the EP group vs. +0.22 +/- 0.09 mU/ml in the C group, P<.05) after 1 year. CONCLUSIONS: Epalrestat suppressed the deterioration of diabetic peripheral neuropathy, especially in the lower extremity. Its effects might be mediated by improvement of the polyol pathway and suppression of production of AGEs.

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Acute interstitial nephritis associated with ulcerative colitis

Tokuyama, H., Wakino, S., Konishi, K., Hashiguchi, A., Hayashi, K. and Itoh, H.

Clin Exp Nephrol 14 ( 5 ) 483 - 6 2010.10

ISSN 1342-1751

Although drugs used in inflammatory bowel diseases (IBD) cause renal injury, glomerulopathies may also accompany IBD. We report a case with the rare association of ulcerative colitis (UC) and acute progressive interstitial nephritis. Although the kidney is acknowledged as a target organ for injury as a result of drug nephrotoxicity, our findings lend support to the novel recognition that the deranged autoimmune system emerging in UC causes interstitial nephritis as an extraintestinal manifestation. Overt renal failure due to interstitial nephritis has rarely been reported in UC patients. The case presented here therefore provides novel information on UC-associated nephropathy.

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