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Papers - Ito, Hiroshi

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Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver

Tagawa, H., Irie, J., Itoh, A., Kusumoto, Y., Kato, M., Kobayashi, N., Tanaka, K., Morinaga, R., Fujita, M., Nakajima, Y., Morimoto, K., Sugizaki, T., Kawano, Y., Yamada, S., Kawai, T., Watanabe, M. and Itoh, H.

Diabetes Res Clin Pract 109 ( 1 ) 85 - 94 2015.07

ISSN 0168-8227

AIMS: Bile acid binding resin (BAR) improves glycaemic control in patients with type 2 diabetes. Although the mechanism is hypothesised to involve the clearance of excess hepatic triglyceride, this hypothesis has not been examined in appropriately designed studies. Therefore, we investigated whether reduced hepatic triglyceride deposition is involved in BAR-mediated improvements in glycaemic control in spontaneous fatty liver diabetic mice without dietary interventions. METHODS: Male 6-week-old fatty liver Shionogi (FLS) mice were fed a standard diet without or with 1.5% BAR (colestilan) for 6 weeks. Glucose tolerance, insulin sensitivity, hepatic lipid content, and gene expression were assessed. A liver X receptor (LXR) agonist was also administered to activate the LXR pathway. We also retrospectively analysed the medical records of 21 outpatients with type 2 diabetes who were treated with colestilan for >/=6 months. RESULTS: BAR enhanced glucose tolerance and insulin sensitivity in FLS mice without altering fat mass. BAR improved hepatic insulin sensitivity, increased IRS2 expression, and decreased SREBP expression. BAR reduced hepatic cholesterol levels but not hepatic triglyceride levels. BAR also reduced the expression of LXR target genes, and LXR activation abolished the BAR-mediated improvements in glycaemic control. Colestilan significantly lowered serum cholesterol levels and improved glycaemic control in patients with type 2 diabetes. CONCLUSIONS: BAR improved hepatic insulin resistance in FLS mice by reducing hepatic cholesterol without affecting hepatic triglyceride levels or body fat distribution. Our study revealed that BAR improves glycaemic control at least in part by downregulating the hepatic cholesterol-LXR-IRS2 pathway.

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Transcription factors and epigenetic modulation: its therapeutic implication in chronic kidney disease

Hayashi, K. and Itoh, H.

Arch Immunol Ther Exp (Warsz) 63 ( 3 ) 193 - 6 2015.06

ISSN 0004-069

Recently emerging evidence has shown that epigenetic mechanisms are involved in initiation and progression of various diseases, including kidney diseases. In the present article, we review the current data regarding the role of epigenetic modulation in chronic kidney disease (CKD) and kidney fibrosis, including DNA methylation and histone modification. Especially we focused on the role of transcription factors in epigenetic modulation and the possibility of therapeutic target of CKD. We have recently reported that transcription factor Kruppel-like factor 4 (also known as gut-enriched Kruppel-like factor) is expressed in kidney podocytes (visceral epithelial cells) and modulates podocyte phenotype by gene-selective epigenetic control. Targeting transcription factors for epigenetic modification may be a good candidate for remission and regression of CKD. It is necessary for the therapy of CKD with an epigenetic-based approach to investigate organ-, tissue-, or gene-specific treatment methods for reduction of side effects.

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CT during Arteriography to Visualize the Right Adrenal Vein for Adrenal Venous Sampling

Oguro, S., Nakatsuka, S., Yashiro, H., Hashimoto, S., Miyashita, K., Kurihara, I., Itoh, H. and Jinzaki, M.

J Vasc Interv Radiol 26 ( 6 ) 910 - 4 2015.06

ISSN 1051-0443

The present report describes 6 cases of adrenal venous sampling (AVS) in patients who underwent computed tomography (CT) during arteriography because cannulation of right adrenal veins was otherwise difficult. CT was performed during arteriography to obtain information on the location and direction of the right adrenal vein. Two right adrenal veins were visualized in 1 case. The right central adrenal vein was not visualized in 1 case owing to an injury from a previous unsuccessful AVS procedure, but the right renal capsular vein was well visualized. CT during arteriography could contribute to a high AVS success rate.

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C-peptide immunoreactivity index is associated with improvement of HbA1c: 2-Year follow-up of sitagliptin use in patients with type 2 diabetes

Nishimura, T., Meguro, S., Sekioka, R., Tanaka, K., Saisho, Y., Irie, J., Tanaka, M., Kawai, T. and Itoh, H.

Diabetes Res Clin Pract 108 ( 3 ) 441 - 7 2015.06

ISSN 0168-8227

AIMS: This retrospective study aimed to determine the hypoglycaemic effect of 2 years of sitagliptin administration in terms of changes in HbA1c and C-peptide immunoreactivity (CPR) index (plasma CPR [ng/mL]/glucose [mg/dL]x100). METHODS: The inclusion criteria for DPP-4 inhibitor-naive outpatients with type 2 diabetes (n=285) were: continuation of sitagliptin for >/=700 days from initial administration and measurement of HbA1c, serum CPR, and plasma glucose levels at 0, 3, 6, 12, 18, and 24 months after sitagliptin initiation. Logistic regression analyses determined the factors contributing to the response to sitagliptin, based on responder (DeltaHbA1c </=-0.4% [</=-4 mmol/mol]) and non-responder (DeltaHbA1c >-0.4% [>-4 mmol/mol]) groups. RESULTS: The HbA1c level decreased and CPR index increased from baseline to 3, 6, 12, 18, and 24 months after the start of sitagliptin administration (HbA1c: 7.4 +/- 0.8% [57 +/- 9 mmol/mol], 7.3 +/- 0.9% [57 +/- 9 mmol/mol], 7.4 +/- 0.9% [58 +/- 10 mmol/mol], 7.1 +/- 0.8% [55 +/- 9 mmol/mol], and 7.3 +/- 0.9% [57 +/- 10 mmol/mol], respectively, all P<0.001 vs. baseline [8.0 +/- 1.0%, 64 +/- 11 mmol/mol] and CPR index: 1.69 +/- 0.96, 1.71 +/- 1.10, 1.62 +/- 0.96, 1.64 +/- 0.92, and 1.66 +/- 0.96, respectively, all P<0.05 vs. baseline [1.47 +/- 0.81]). Higher baseline HbA1c level, shorter diabetes duration, and greater CPR index increase after sitagliptin administration were associated with the response to sitagliptin. CONCLUSIONS: Our results suggest that sitagliptin improves glycaemic control via an improved intrinsic insulin response.

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Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans

Hosoya, K., Minakuchi, H., Wakino, S., Fujimura, K., Hasegawa, K., Komatsu, M., Yoshifuji, A., Futatsugi, K., Shinozuka, K., Washida, N., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Kidney Int 87 ( 4 ) 749 - 60 2015.04

ISSN 0085-2538

In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.

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Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia after treatment with atorvastatin

Homma, K., Homma, Y., Yoshida, T., Ozawa, H., Shiina, Y., Wakino, S., Hayashi, K., Itoh, H. and Hori, S.

J Clin Lipidol 9 ( 2 ) 210 - 6 2015.03

ISSN 1933-2874

BACKGROUND: Plasma levels of low-density lipoproteins (LDLs) are decreased through stimulation of their hepatic uptake by statins via an LDL receptor. However, it is unclear whether statins equally stimulate the hepatic uptake of all LDL subfractions. OBJECTIVE: We compared the effects of atorvastatin on 3 LDL subfractions, and their associations with LDL-receptor activities, in Japanese patients with polygenic hypercholesterolemia (PHC), familial combined hyperlipoproteinemia (FCHL), and familial hypercholesterolemia (FH). MATERIALS AND METHODS: Atorvastatin was administered to patients with PHC (n = 11), FCHL (n = 16), and FH (n = 13). We measured plasma levels of lipids, remnant-like particle cholesterol, apoproteins, and cholesterol in lipoprotein fractions. Sequential ultracentrifugation was performed to subfractionate the plasma lipoproteins, and lymphocyte LDL-receptor activities were estimated using flow cytometry. RESULTS: The average daily dosage of atorvastatin was 10, 27, and 40 mg in patients with PHC, FCHL, and FH, respectively; after 12 months of atorvastatin treatment, LDL cholesterol (LDL-C) plasma levels decreased by 44%, 50%, and 53%, respectively (all, P < .0001). Atorvastatin reduced low-density LDL-C plasma levels in patients with PHC (48% reduction), FCHL (53%), and FH (46%) (all, P < .0001). Plasma levels of medium-density and high-density LDL-C were also significantly reduced in the 3 patient groups (all, P </= .0147). LDL-receptor activity was negatively correlated with baseline levels of medium-density LDL-C and with the decreases in plasma md-LDL-C levels. CONCLUSION: Atorvastatin decreased the levels of the 3 LDL fractions. The md-LDL decrease appeared to be mainly because of stimulation of LDL-receptor activity.

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Serum total bilirubin concentration is negatively associated with increasing severity of retinopathy in patients with type 2 diabetes mellitus

Sekioka, R., Tanaka, M., Nishimura, T. and Itoh, H.

J Diabetes Complications 29 ( 2 ) 218 - 21 2015.03

ISSN 1056-8727

AIMS: Serum bilirubin concentration is associated with diabetic retinopathy in patients with type 2 diabetes. This study investigated the relationships between serum bilirubin concentration and the severity of diabetic retinopathy. In addition, the importance of bilirubin was compared with factors that were previously shown to be associated with the incidence of diabetic retinopathy. METHODS: A total of 674 patients with type 2 diabetes were investigated in this cross-sectional study. Serum total bilirubin concentration was compared between patients with and without diabetic retinopathy, and according to the severity of retinopathy. Univariate and multivariate analyses were performed to evaluate the association of retinopathy with total bilirubin concentration, duration of diabetes, body mass index, systolic blood pressure, and haemoglobin A1c. RESULTS: Serum total bilirubin concentration was significantly lower in patients with retinopathy than in those without. Patients with severer retinopathy showed lower total bilirubin concentration, longer diabetes duration, and higher systolic blood pressure. These three parameters were independent explanatory factors for diabetic retinopathy. CONCLUSIONS: Total bilirubin concentration is lower in patients with type 2 diabetes complicated with severer retinopathy. Thus, bilirubin might protect against retinopathy in patients with type 2 diabetes.

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Impact of Peritoneal Dialysis Catheter Insertion by a Nephrologist: Results of a Questionnaire Survey of Patients and Nurses

Washida, N., Aikawa, K., Inoue, S., Kasai, T., Shinozuka, K., Morimoto, K., Hosoya, K., Hayashi, K. and Itoh, H.

Adv Perit Dial 31 59 - 68 2015

ISSN 1197-8554

Peritoneal dialysis (PD) is an excellent dialysis mo- dality, but it is underutilized in the United States and Japan. In the present study, we evaluated the impact of interventional nephrology in PD on the impres- sions held by patients and nurses about selection of a renal replacement therapy and the complications associated with PD therapy. Over aperiod of 7 years, PD catheter insertion in 120 patients with end-stage renal disease (age: 63.0 +/- 13.3 years) was performed by nephrologists at Keio University Hospital or Saitama Medical Center. A questionnaire survey evaluating the advantages and disadvantages of this interventional nephrology approach in PD was distributed to 72 PD patients and to 53 nurses in charge of those patients. After interventional nephrology in PD was adopted, the number of patients selecting PD therapy increased. The incidence of peritonitis was relatively low (1 episode in 101.1 patient-months). Responses to the questionnaire survey showed that neither patients nor nurses were concerned about catheter insertion by physicians, and no communication problems between the patients, nurses, and physicians were reported. Approximately 60% of the nurses specializing in PD therapy showed higher motivation with interventional nephrology, which might have a favorable effect on the selection of PD therapy, on the incidence of peritonitis, and on the tripartite communication between patients, nurses, and physicians.

Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes

Tanaka, K., Saisho, Y., Kawai, T., Tanaka, M., Meguro, S., Irie, J., Imai, T., Shigihara, T., Morimoto, J., Yajima, K., Atsumi, Y., Takei, I. and Itoh, H.

Endocr J 62 ( 5 ) 399 - 409 2015

ISSN 0918-8959

There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 +/- 0.80% vs. -0.80 +/- 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM.

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Efficacy and safety of sitagliptin added to insulin in Japanese patients with type 2 diabetes: the EDIT randomized trial

Sato, S., Saisho, Y., Kou, K., Meguro, S., Tanaka, M., Irie, J., Kawai, T. and Itoh, H.

PLoS One 10 ( 3 ) e0121988 2015

ISSN 1932-6203

AIMS: To clarify the efficacy and safety of adding sitagliptin to insulin therapy in Japanese patients with suboptimally controlled type 2 diabetes (T2DM). STUDY DESIGN AND METHODS: This was a 24-week, prospective, randomized, open-labeled, controlled trial. Patients with T2DM who were suboptimally controlled despite receiving at least twice daily injection of insulin were enrolled in the study. The patients were randomized to continuation of insulin treatment (Insulin group) or addition of sitagliptin 50 to 100 mg daily to insulin treatment (Ins+Sita group). The primary outcome was change in HbA1c at week 24. RESULTS: Adding sitagliptin to insulin significantly reduced HbA1c from 7.9 +/- 1.0% at baseline to 7.0 +/- 0.8% at week 24 (P <0.0001), while there was no significant change in HbA1c in the Insulin group (7.8 +/- 0.7% vs. 7.8 +/- 1.1%, P = 0.32). The difference in HbA1c reduction between the groups was 0.9% (95% confidence interval, 0.4 to 1.5, P = 0.01). There was no significant weight gain in either group. Incidence of hypoglycemia was significantly reduced in the Ins+Sita group compared with the Insulin group. Treatment satisfaction was improved in the Ins+Sita group. Baseline HbA1c level and beta cell function were associated with the magnitude of reduction in HbA1c in the Ins+Sita group. CONCLUSION: Adding sitagliptin to insulin reduced HbA1c without weight gain or increase in hypoglycemia, and improved treatment satisfaction in Japanese patients with T2DM who were suboptimally controlled despite at least twice daily injection of insulin. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004678.

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A Reduction of HbA1c after 3 Months Predicts 2-year Responsiveness to Sitagliptin Treatment

Nishimura, T., Meguro, S., Sekioka, R., Tanaka, K., Saisho, Y., Irie, J., Tanaka, M., Kawai, T. and Itoh, H.

Intern Med 54 ( 23 ) 2981 - 9 2015

ISSN 0918-2918

OBJECTIVE: This retrospective study evaluated the long-term efficacy of sitagliptin and the factors contributing to its glucose-lowering effect. METHODS: Six hundred and sixteen dipeptidyl peptidase-4 inhibitor-naive outpatients with type 2 diabetes who began sitagliptin treatment between December 1, 2009 and December 31, 2011 were included in this study. The inclusion criteria were that the patient had regularly visited our hospital for a period of >/=700 days from the initiation of sitagliptin treatment and the measurement of hemoglobin A1c (HbA1c) had been performed at 0, 3, 6, 12, 18, and 24 months after the initiation of treatment. From the population of 616 patients, 447 and 169 had received sitagliptin for >/=700 and <700 days, respectively. The primary endpoint was DeltaHbA1c at 24 months. The factors associated with the hypoglycemic effect of sitagliptin were also investigated. RESULTS: Sitagliptin treatment significantly decreased the level of HbA1c, and the hypoglycemic effect was sustained for at least 2 years. The baseline HbA1c level, duration of diabetes, Deltabody weight value, and DeltaHbA1c value at 3 months were independently associated with the hypoglycemic effect of sitagliptin. CONCLUSION: Sitagliptin has a long-term hypoglycemic effect in type 2 diabetes patients. A patient's DeltaHbA1c at 3 months may be a predictor of their DeltaHbA1c at 24 months.

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Role of endogenous ACTH on circadian aldosterone rhythm in patients with primary aldosteronism

Sonoyama, T., Sone, M., Tamura, N., Honda, K., Taura, D., Kojima, K., Fukuda, Y., Kanamoto, N., Miura, M., Yasoda, A., Arai, H., Itoh, H. and Nakao, K.

Endocr Connect 3 ( 4 ) 173 - 9 2014.12

ISSN 2049-3614

We recently reported that stimulation with high-dose ACTH caused different responses in terms of aldosterone secretion in aldosterone-producing adenomas (APAs) and idiopathic hyperaldosteronism (IHA) in patients with primary aldosteronism (PA). However, the role of endogenous ACTH in aldosterone secretion in PA has not been systematically evaluated. In this study, we examined diurnal changes in plasma aldosterone concentration (PAC), and changes in PAC after dexamethasone administration in patients with suspected PA, in order to evaluate the effect of endogenous ACTH on aldosterone secretion. Seventy-three patients admitted to Kyoto University Hospital with suspected PA were included. The patients were classified into non-PA, IHA, and APA groups according to the results of captopril challenge test and adrenal venous sampling. PAC at 0900 h (PAC0900), 2300 h (PAC2300), and after 1-mg dexamethasone suppression test (PACdex) was measured and compared among the three groups. The PAC2300/PAC0900 and PACdex/PAC0900 ratios were also analyzed. PAC2300 and PACdex were lower than PAC0900 in all three groups. There were no significant differences in PAC2300/PAC0900 among the three groups. However, PACdex/PAC0900 was significantly lower in the APA group compared with the non-PA and IHA groups. The results of this study indicate that aldosterone secretion in APA patients is more strongly dependent on endogenous ACTH than in IHA and non-PA patients. The results also suggest that factors other than ACTH, such as clock genes, may cause diurnal changes in aldosterone secretion in IHA and non-PA patients.

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Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: association with BNP and aldosterone levels

Tanaka, M., Sekioka, R., Nishimura, T., Ichihara, A. and Itoh, H.

Diabetes Res Clin Pract 106 ( 3 ) 504 - 10 2014.12

ISSN 0168-8227

AIMS: Hypertension stimulates the sympathetic nervous system and this phenomenon is exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus. METHODS: In 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidipine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary albumin excretion ratio in the same patients by a cross-over design. Other biochemical parameters were also evaluated. RESULTS: Switching to cilnidipine did not change blood pressure but caused reduction in catecholamine concentrations in blood and urine and plasma aldosterone concentration, accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid binding protein, and albumin excretion ratio. These parameters other than brain natriuretic peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker. CONCLUSIONS: In 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin-angiotensin-aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus.

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Relationship between body mass index and pancreas volume in Japanese people

Kou, K., Saisho, Y., Jinzaki, M. and Itoh, H.

Jop 15 ( 6 ) 626 - 7 2014.11

ISSN 1590-8577

CONTEXT: The volume of the pancreas increases with obesity. OBJECTIVE: This study was aimed to explore the relationship between body mass index (BMI) and pancreas volume in Japanese. METHODS: The pancreas volume was examined in a total of 103 (60 men and 43 women) Japanese adults who had undergone abdominal computed tomography (CT) scan. The pancreas was outlined by hand in each CT image and the pancreas volume was computed by summing the product of pancreas area of each image and the CT section thickness. RESULTS: There was a significant positive correlation between BMI and pancreas volume (r = 0.41, P <0.001). This relationship was expressed by the following equation: y = 23.8 + 2.48x, where y is pancreas volume (cm3) and x is BMI. CONCLUSIONS: There is a positive correlation between BMI and pancreas volume in Japanese and this relationship is similar to that in Caucasians. This information will be useful to estimate the impact of obesity on pancreas volume in Japanese and for comparison among different ethnicities.

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Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

Matsuura, T., Wakino, S., Yoshifuji, A., Nakamura, T., Tokuyama, H., Hashiguchi, A., Konishi, K., Iwasa, T., Shoji, M., Hosono, A., Ohashi, K., Chuman, H. and Itoh, H.

CEN Case Rep 3 ( 2 ) 226 - 231 2014.11

ISSN 2192-4449

Long-term nephrotoxicity of ifosfamide is occasionally progressive, and, in such case, there has been no specific treatment to prevent progression. It has been reported that the presence of karyomegalic interstitial nephritis, which is rare type of interstitial nephritis, may be related to ifosfamide-induced nephropathy with poor prognosis and resistant to the immunosuppressive therapy. A 15-year-old boy presented with progressive nephrotoxicity 3 years after systemic chemotherapy with ifosfamide and cisplatin for the treatment of osteosarcoma. Renal biopsy revealed the severe tubulointerstitial nephritis with tubular atrophy and focal global and segmental glomerular sclerosis. It also showed tubular epithelial cells with variably sized nuclei, some of which were massively enlarged, abnormal hyperchromatic, irregular shaped, and bizarre-appearing. These morphological changes were suggestive of the histology of karyomegalic interstitial nephritis. Corticosteroid retarded the progression of nephrotoxicity. The present case is the first report, suggesting that corticosteroid was effective against the late-onset renal toxicity by ifosfamide therapy. Our case also suggests that karyomegalic interstitial nephritis may be the result of long-term nephrotoxicity of ifosfamide. Since concurrent treatment with cisplatin is one of the risk factors for ifosfamide nephrotoxicity, there is a possibility that cisplatin may have a synergetic effect with ifosfamide for producing karyomegalic interstitial nephritis.

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Renal arteriolar injury by salt intake contributes to salt memory for the development of hypertension

Oguchi, H., Sasamura, H., Shinoda, K., Morita, S., Kono, H., Nakagawa, K., Ishiguro, K., Hayashi, K., Nakamura, M., Azegami, T., Oya, M. and Itoh, H.

Hypertension 64 ( 4 ) 784 - 91 2014.10

ISSN 0194-911

The role of salt intake in the development of hypertension is prominent, but its mechanism has not been fully elucidated. Our aim was to examine the effect of transient salt intake during the prehypertensive period in hypertensive model animals. Dahl salt-sensitive rats and spontaneously hypertensive rats were fed from 6 to 14 weeks with low-salt (0.12% NaCl), normal-salt (0.8% NaCl), high-salt (7% NaCl), or high-sodium/normal-chloride diet and returned to normal-salt diet for 3 months. Rats in the high-salt group saw elevations in blood pressure (BP) not only during the treatment period but also for the 3 months after returning to normal-salt diet. We named this phenomenon salt memory. Renal arteriolar injury was found in the high-salt group at the end of experiment. Dahl salt-sensitive rats were fed from 6 to 14 weeks with high-salt diet with angiotensin receptor blocker, vasodilator, calcium channel blocker, and calcium channel blocker+angiotensin receptor blocker and returned to normal-salt diet. Although BP was suppressed to control levels by vasodilator or calcium channel blocker, elevated renal angiotensin II and renal arteriolar injury were observed, and salt memory did not disappear because of sustained renal arteriolar injury. Calcium channel blocker+angiotensin receptor blocker suppressed renal arteriolar injury, resulting in the disappearance of salt memory. Cross-transplantation of kidneys from Dahl salt-sensitive rats on high salt to control rats caused increase of BP, whereas control kidneys caused reduction in BP of hypertensive rats, inducing the central role of the kidney. These results suggest that renal arteriolar injury through BP and renal angiotensin II elevation plays important roles in the development of salt memory for hypertension.

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Significant roles of the (pro)renin receptor in integrity of vascular smooth muscle cells

Kurauchi-Mito, A., Ichihara, A., Bokuda, K., Sakoda, M., Kinouchi, K., Yaguchi, T., Yamada, T., Sun-Wada, G. H., Wada, Y. and Itoh, H.

Hypertens Res 37 ( 9 ) 830 - 5 2014.09

ISSN 0916-9636

The (pro)renin receptor ((P)RR) is known to play an important role in the pathogenesis of vascular complications in diabetes mellitus and hypertension through its function in activating the local renin-angiotensin system. Recent studies have shown that the (P)RR is an accessory protein of the vacuolar H(+)-ATPase, suggesting a more fundamental and developmental function. In this study, smooth muscle cell-specific (P)RR/Atp6ap2 conditional knockout mice were generated. Smooth muscle cell-specific ablation of the (P)RR resulted in nonatherogenic sclerosis in the abdominal aorta. The deletion of the (P)RR did not affect ambulatory blood pressure levels. In cultured murine vascular smooth muscle cells (VSMCs), ablation of the (P)RR suppressed the expression of the Vo subunit c of the vacuolar H(+)-ATPase and impaired the cell recycling system, leading to autophagic cell death. In addition, loss of the (P)RR in VSMCs induced the expression of monocyte chemotactic protein-1 and interleukin-6 mRNAs. These results suggest that the (P)RR is essential for cell survival and downregulation of vascular inflammation in murine VSMCs through maintaining normal function of the vacuolar H(+)-ATPase.

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Serum creatinine and albumin decline predict the contraction of nosocomial aspiration pneumonia in patients undergoing hemodialysis

Minakuchi, H., Wakino, S., Hayashi, K., Inamoto, H. and Itoh, H.

Ther Apher Dial 18 ( 4 ) 326 - 33 2014.08

ISSN 1744-9979

Aspiration pneumonia (AP) is prevalent in older adults and the hemodialysis (HD) population has been getting older. Therefore, it is speculated that increasing number of HD patients would suffer from AP. However, the clinical aspects of AP in HD patients have not been elucidated. Consecutive HD patients with nosocomial AP hospitalized in our university hospital from April 2007 to December 2008 were recruited. Their clinical characteristics, risk factors for contraction, and the fatality of AP and treatment options were described. Nineteen out of 356 hospitalized HD patients had AP and 8 out of 19 AP patients died, indicating the incidence rate and fatality rate were 5.34% and 42.1%, respectively. Multiple regression analysis revealed that the risk factors for contracting AP included age, body mass index, serum creatinine levels (Cre) and the monthly decline rate of Cre. It also revealed that serum albumin (Alb) and basal total cholesterol levels, the decline rate of Alb and Cre levels, and the duration of AP were independent risk factors for fatality. Survivors were most often treated with tube feeding. Both contraction rate and fatality of nosocomial AP were high among HD patients. Both the malnutrition as well as the decline rate for nutrition and muscle volume indicated by falls in Alb and Cre, respectively, had clinical relevance in AP. Maintaining nutritional state by tube feeding and muscle volume seems to be the mainstay for the prevention and the treatment of AP in HD patients.

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The Niemann-Pick C1 like 1 (NPC1L1) inhibitor ezetimibe improves metabolic disease via decreased liver X receptor (LXR) activity in liver of obese male mice

Sugizaki, T., Watanabe, M., Horai, Y., Kaneko-Iwasaki, N., Arita, E., Miyazaki, T., Morimoto, K., Honda, A., Irie, J. and Itoh, H.

Endocrinology 155 ( 8 ) 2810 - 9 2014.08

ISSN 0013-7227

Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-A(y) mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic beta-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome.

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Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase

Tamaki, M., Miyashita, K., Wakino, S., Mitsuishi, M., Hayashi, K. and Itoh, H.

Kidney Int 85 ( 6 ) 1330 - 9 2014.06

ISSN 0085-2538

Chronic kidney disease impairs physical performance. Here the time course and mechanism of muscle insufficiency in renal failure and the influence of dietary protein were studied using 5/6 nephrectomized C57Bl/6 mice, focusing on muscle mass and mitochondria. A decrease in muscle mitochondria and running distance was found in young (16-20 weeks) 5/6 nephrectomized mice, despite the preservation of muscle volume and power. However, a decrease in muscle volume, associated with a reduction in muscle power, was found in aged (48-52 weeks) 5/6 nephrectomized mice. A high-protein diet feeding from 8 weeks increased muscle volume and power in the mice; but this further decreased running distance. Activation of pyruvate dehydrogenase by dichloroacetate effectively recovered running distance that was decreased by dietary protein. These findings indicate the mechanism of muscle insufficiency in renal failure and suggest that activation of muscle mitochondria would serve as a potential strategy for improving the physical performance of the patients with chronic kidney disease.

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