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Objective. We examined whether or not day-to-day variations in lipid profiles, especially triglyceride (TG) variability, were associated with the exacerbation of diabetic kidney disease. Methods. We conducted a retrospective and observational study. First, 527 patients with type 2 diabetes mellitus (DM) who had had their estimated glomerular filtration rate (eGFR) checked every 6 months since 2012 for over 5 years were registered. Variability in postprandial TG was determined using the standard deviation (SD), SD adjusted (Adj-SD) for the number of measurements, and maximum minus minimum difference (MMD) during the first three years of follow-up. The endpoint was a ≥40% decline from baseline in the eGFR, initiation of dialysis or death. Next, 181 patients who had no micro- or macroalbuminuria in February 2013 were selected from among the 527 patients for an analysis. The endpoint was the incidence of microalbuminuria, initiation of dialysis, or death. Results. Among the 527 participants, 110 reached a ≥40% decline from baseline in the eGFR or death. The renal survival was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p = 0.0073 , 0.0059, and 0.0195, respectively). A lower SD, lower Adj-SD, and lower MMD were significantly associated with the renal survival in the adjusted model (hazard ratio, 1.62, 1.66, 1.59; 95% confidence intervals, 1.05-2.53, 1.08-2.58, 1.04-2.47, respectively). Next, among 181 participants, 108 developed microalbuminuria or death. The nonincidence of microalbuminuria was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p = 0.0241 , 0.0352, and 0.0474, respectively). Conclusions. Postprandial TG variability is a novel risk factor for eGFR decline and the incidence of microalbuminuria in patients with type 2 DM.

Objective: The prevention of chronic kidney disease (CKD) progression is an important issue from health and financial perspectives. We conducted a single-year cross-sectional study to clarify the prevalence of CKD and its risk factors along with variations in these factors among five medical regions in Okayama Prefecture, Japan. Methods and Results: Data concerning the renal function and proteinuria as well as other CKD risk factors were obtained from the database of the Japanese National Health Insurance. The proportion of CKD patients at an increased risk of progression to end-stage renal disease (ESRD), classified as orange and red on the CKD heatmap, ranged from 6–9% and did not vary significantly by the regions. However, the causes of the increased severity differed between regions where renal dysfunction was predominant and regions where there were many patients with proteinuria. CKD risk factors, such as diabetes mellitus, hypertension, hyper low-density lipoprotein-cholesterolemia, obesity, smoking and lack of exercise, also differed among these regions, suggesting that different regions need tailored interventions that suit the characteristics of the region, such as an increased health checkup ratio, dietary guidance and promotion of exercise opportunities. Conclusions: Approximately 6–9% of people are at an increased risk of developing ESRD (orange or red on a CKD heatmap) among the population with National Health Insurance in Okayama Prefecture. The underlying health problems that cause CKD may differ among the regions. Thus, it is necessary to consider intervention methods for preventing CKD progression that are tailored to each region’s health problems.

Background: Chronic angiotensin II (AngII) infusion promotes ascending aortic dilation in C57BL/6J mice. Meanwhile, vasohibin-2 (VASH2) is an angiogenesis promoter in neovascularization under various pathologic conditions. The aim of this study was to investigate whether exogenous VASH2 influences chronic AngII-induced ascending aortic dilation. Methods and Results: Eight–ten-week-old male C57BL/6J mice were injected with adenovirus (Ad) expressing either VASH2 or LacZ. One week after the injection, mice were infused with either AngII or saline s.c. for 3 weeks. Mice were divided into 4 groups: AngII+VASH2, AngII+LacZ, saline+VASH2, and saline+LacZ. Overexpression of VASH2 significantly increased AngII-induced intimal areas as well as the external diameter of the ascending aorta. In addition, VASH2 overexpression promoted ascending aortic medial elastin fragmentation in AngII-infused mice, which was associated with increased matrix metalloproteinase activity and medial smooth muscle cell (SMC) apoptosis. On western blot analysis, accumulation of apoptotic signaling proteins, p21 and p53 was increased in the AngII+VASH2 group. Furthermore, transfection of human aortic SMC with Ad VASH2 increased p21 and p53 protein abundance upon AngII stimulation. Positive TUNEL staining was also detected in the same group of the human aortic SMC. Conclusions: Exogenous VASH2 exacerbates AngII-induced ascending aortic dilation in vivo, which is associated with increased medial apoptosis and elastin fragmentation.

Cardiac fibrosis is characterized by the net accumulation of extracellular matrix in the myocardium and is an integral component of most pathological cardiac conditions. Cilostazol, a selective inhibitor of phosphodiesterase type III with anti-platelet, anti-mitogenic, and vasodilating properties, is widely used to treat the ischemic symptoms of peripheral vascular disease. Here, we investigated whether cilostazol has a protective effect against Angiotensin II (AngII)-induced cardiac fibrosis. Male apolipoprotein E-deficient mice were fed either a normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, the mice were infused with saline or AngII (1000 ng kg−1 min−1) for 28 days. AngII infusion increased heart/body weight ratio (p < 0.05), perivascular fibrosis (p < 0.05), and interstitial cardiac fibrosis (p < 0.0001), but were significantly attenuated by cilostazol treatment (p < 0.05, respectively). Cilostazol also reduced AngII-induced increases in fibrotic and inflammatory gene expression (p < 0.05, respectively). Furthermore, cilostazol attenuated both protein and mRNA abundance of osteopontin induced by AngII in vivo. In cultured human cardiac myocytes, cilostazol reduced mRNA expression of AngII-induced osteopontin in dose-dependent manner. This reduction was mimicked by forskolin treatment but was cancelled by co-treatment of H-89. Cilostazol attenuates AngII-induced cardiac fibrosis in mice through activation of the cAMP–PKA pathway.

Aim Since 1998, the leading cause of chronic hemodialysis in Japan has been diabetic nephropathy. Diabetes mellitus is known to be a risk factor for frailty, but it still remains unknown whether diabetic nephropathy is associated with frailty in chronic dialysis patients. The authors carried out the present study to reveal the association between frailty and diabetic nephropathy in chronic hemodialysis patients. Methods A total of 355 patients who were on hemodialysis were recruited. Participants were divided into two groups of either patients who suffered diabetic nephropathy with end-stage renal disease (DN group, n = 150) or not (Non-DN group, n = 205). The authors investigated the difference of the prevalence of frailty between the two groups. Furthermore, the authors examined the risk factors for frailty. Results The prevalence of frailty in the DN group was significantly higher than that in the Non-DN group (28.0% vs 16.5%, P = 0.0161). To evaluate the association between frailty and its risk factors, we compared frail patients (n = 71) and non-frail patients (n = 262). After adjusting their interrelationships by using multivariate logistic regression analysis, diabetic nephropathy was determined as a significant risk factor for frailty. Conclusions The authors found the close association between frailty and diabetic nephropathy in chronic hemodialysis patients. Geriatr Gerontol Int 2018; 18: 1597-1602.

ObjectivesThe clinical condition of frailty is a common problem in the elderly population. However, the relationship between peripheral artery disease and frailty in hemodialysis patients remains unknown. The aim of this study was to identify the relationships between peripheral artery disease and frailty in Japanese chronic hemodialysis patients.MethodsA total of 362 chronic hemodialysis patients who regularly visited six institutions were enrolled. To evaluate frailty, the modified Fried’s frailty phenotype adjusted for Japanese were used. Peripheral artery disease was defined as ankle-brachial index ResultsOf 362 patients, 62 patients (17.1%) were categorized as peripheral artery disease group and 300 patients (82.9%) as Non-peripheral artery disease group. The prevalence of frailty in the peripheral artery disease group was significantly higher than in the Non-peripheral artery disease group (34% vs. 18%, P = 0.0103). Non-shunt side grip strength was significantly stronger in the Non-peripheral artery disease group (23.6 kg vs. 17.0 kg, P ConclusionsIt is concluded that peripheral artery disease is closely associated with frailty in hemodialysis patients.

Yuki Kakio,1 Haruhito A Uchida1,2Hidemi Takeuchi,1 Yuka Okuyama,1 Ryoko Umebayashi,1 Hiroyuki Watatani,1 Yohei Maeshima,1 Hitoshi Sugiyama,1 Jun Wada11Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 2Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JapanBackground: From 2011, Okayama municipal government started the health checkup follow-up project to find those who were unaware of suffering chronic kidney disease and to prevent from aggravation of CKD stage. In this study, we aimed to evaluate the effect of 2 years’ CKD-follow-up project regarding renal function and CKD risks.Patients and methods: Those who received a health checkup by the national health insurance in Okayama city in 2011 were recruited. The patients with lifestyle-related diseases or metabolic syndrome were excluded. Subjects who had an estimated glomerular filtration rate

This study aimed to clarify the relationship between repeated measurements of casual (spot) and 24-h urinary sodium-to-potassium (Na/K) ratios in patients with chronic kidney disease (CKD). A total of 61 inpatients with CKD, 31 in stage 1-3 (eGFR [estimated glomerular filtration rate] ≥ 30 ml/min/1.73 m2) and 30 in stage 4-5 (eGFR < 30 ml/min/1.73 m2), aged 20-85 consuming a low-sodium diet (NaCl [sodium chloride] 6 g/day) were recruited. Urinary Na, K, and Na/K ratios were measured in both casual urine samples and 2-day, 24 h urine samples, and then analyzed by correlation and Bland-Altman analyses. Mean 24-h urine Na/K ratio was higher in participants in stage 4-5 (5.1) than in participants in stage 1-3 (4.1) CKD. Casual urine Na/K ratio was strongly correlated with 2-day, 24-h urine Na/K ratio by sampling 4 casual urine specimens every morning and evening in participants in stage 1-3 (r = 0.69-0.78), but not in stage 4-5 (r = 0.12-0.19). The bias for mean Na/K ratio between 2-day, 24-h urine, and the 4 casual urine sampling ranged from -0.86 to 0.16 in participants in stage 1-3, and the quality of agreement for the mean of this casual urine sampling was similar to that of sampling 8 casual urine samples for estimating 2-day, 24-h values. Methods using repeated casual urine Na/K ratios may provide a reasonable estimation of 24-h urine Na/K ratio in normotensive and hypertensive as well as individuals with stage 1-3, but not stage 4-5 CKD.

Objective: Chronic angiotensin II (AngII) infusion promotes both ascending (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Previously, we demonstrated that exogenous vasohibin-2 (VASH-2) exacerbated AngII-induced TAAs in normolipidemic mice. The purpose of this study was to examine whether exogenous VASH-2 influenced AngII-induced AAAs in mice. Methods and Results: In the initial study, male C57BL/6J mice (10 weeks old) were injected with VASH2 or LacZ expressing adenovirus (Ad; 7.5 x 109 vp/100 μ L) via tail vein at 2 week intervals. One week after the first injection, subcutaneous infusion of AngII (1,000 ng/kg/min) by mini osmotic pumps was initiated for 3 weeks. Consequently, mice were divided into 2 groups: AngII + Ad VASH2 in C57BL/6J mice (n=22) and AngII + Ad LacZ in C57BL/6J mice (n=21). VASH-2 overexpression had no effect on systolic blood pressure, heart rate, body weight, or serum total cholesterol concentrations. Exogenous VASH-2 did not affect ex vivo measurements of maximal diameters of abdominal aortas (AngII + Ad VASH2; 1.36 ± 0.39 mm, AngII + LacZ 1.34 ± 0.24 mm, n.s.) in AngII-infused mice. In a subsequent study, male apolipoprotein E-deficient (apoE-/-) mice (9 to 13 weeks old) were injected with VASH2 or LacZ as described for C57BL/6J mice. Consequently, mice were divided into 2 groups: AngII + Ad VASH2 in apoE-/- mice (n=14) and AngII + Ad LacZ in apoE-/- mice (n=14). Similarly, overexpression of VASH-2 had no effect on systolic blood pressure, heart rate, body weight, or serum total cholesterol concentrations in apoE-/- mice. Furthermore, exogenous VASH-2 did not affect ex vivo measurement of maximal diameter of abdominal aorta (AngII + Ad VASH2; 1.70 ± 0.61 mm, AngII + Ad LacZ; 1.61 ± 0.43 mm, n.s.) in AngII-infused apoE-/- mice. Conclusion: Despite our previous demonstration of the effects on TAA, exogenous VASH-2 did not influence AngII-induced AAA formation in either normolipidemic or apoE-/- mice.

Objective: Lowering sodium-to-potassium ratio has been reported to benefit people for hypertension prevention and control in epidemiological studies. Four to seven repeated measurements of casual urine sodium-to-potassium ratio is known to provide high correlation and good agreement quality with less bias to estimate 7-day 24-hour urinary Na/K ratio in normotensive and hypertensive individuals. However, little is known about urinary Na/K ratio in patients with chronic kidney disease (CKD). The aim of this study was to clarify the relationship of the repeated measurement of casual and 24-hour urinary sodium-to-potassium ratio in patients with CKD. Design and Method: A total of 61 inpatients with CKD, 31 in stage 1-3 (eGFR ≥ 30 ml/min/1.73m 2 ) and 30 in stage 4-5 (eGFR < 30 ml/min/1.73m 2 ), aged 20 to 85 under low-sodium diet (NaCl 6 g/day) were recruited in Okayama University hospital. Sodium-to-potassium ratio in casual urine at 4 points/day (first void after rising, each urine after breakfast, lunch or dinner) for 2 days and 2-day 24-hr urine at the same day were measured. Correlation and the quality of agreement by Bland and Altman between casual urine and 24-hour urine samples were analyzed. Results: Mean 24-hour Na and K excretion was lower in participants in stage 4-5 (Na: 87.5 mmol/24h, K: 18.8 mmol/24h) than in participants in stage 1-3 (Na: 99.0 mmol/24h, K: 26.1 mmol/24h), whereas mean 24-hour urine Na/K ratio was higher in participants in stage 4-5 (5.1) than in participants in stage 1-3 (4.1). Casual urine Na/K ratio was strongly correlated with 2-day 24-hour urinary Na/K ratio by sampling 2 casual urine specimens per day for 2 days in participants in stage 1-3 (r = 0.69-0.78), but not in stage 4-5 (r = 0.12-0.19). The bias for mean Na/K ratio between 2-day 24-hour urine and sampling 2 casual urine per day for 2 days in participants in stage 1-3 ranged from -0.86 to 0.16, and the quality of agreement for the mean of this casual urine sampling was similar to that of all 8 points of casual urine samples for estimating 2-day 24-hour values. Conclusion: Repeated casual urine Na/K ratio measurement may provide good estimate of 24-hour urine Na/K ratio, in stage 1-3 CKD patients as well as normotensive and hypertensive people; however, not in stage 4-5 CKD patients.

Objective— Abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta associated with rupture, which frequently results in fatal consequences. AAA tissue is commonly characterized by localized structural deterioration accompanied with inflammation and profound accumulation of leukocytes, although the specific function of these cells is unknown. Cilostazol, a phosphodiesterase III inhibitor, is commonly used for patients with peripheral vascular disease or stroke because of its anti-platelet aggregation effect and anti-inflammatory effect, which is vasoprotective effect. In this study, we evaluated the effects of cilostazol on angiotensin II–induced AAA formation. Approach and Results— Male apolipoprotein E–deficient mice were fed either normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, mice were infused with angiotensin II (1000 ng/kg per minute) for 4 weeks. Angiotensin II infusion increased maximal diameters of abdominal aortas, whereas cilostazol administration significantly attenuated dilatation of abdominal aortas, thereby, reducing AAA incidence. Cilostazol also reduced macrophage accumulation, matrix metalloproteinases activation, and inflammatory gene expression in the aortic media. In cultured vascular endothelial cells, cilostazol reduced expression of inflammatory cytokines and adhesive molecules through activation of the cAMP–PKA (protein kinase A) pathway. Conclusions— Cilostazol attenuated angiotensin II–induced AAA formation by its anti-inflammatory effect through phosphodiesterase III inhibition in the aortic wall. Cilostazol may be a promising new therapeutic option for AAAs.

Objective: The clinical condition of frailty is a common problem in the elderly population. Chronic hemodialysis (HD) patients often have peripheral artery disease (PAD) as a vascular complication. However, the relationship between PAD and frailty in Japanese HD patients remains unknown. The aim of this study was to identify the relationships among PAD and risk factors in Japanese chronic HD patients. Method: This study was a multi-center, cross-sectional and observational investigation which was conducted at 6 institutions, including 5 general hospitals and 1 private clinic. Subjects were all chronic HD patients who regularly visited the institutions. To evaluate frailty, we used the modified Fried’s frailty phenotype adjusted for Japanese as the self-reported questionnaire, and measured each physical domain. Furthermore, we calculated ankle-brachial index (ABI) to define PAD. PAD was defined as ABI < 0.9 in our study. Result: Of the 542 patients in all institutions, 362 were enrolled in this study. Sixty-two patients (17.1%) were categorized as PAD group and 300 patients (82.9%) as non-PAD group. In the PAD group, the prevalence of frailty was significantly higher than in the non-PAD group (34% vs 18%). Non-shunt side grip strength was significantly stronger in the non-PAD group (23.6 kg vs 17.0 kg, P P =0.0054). Univariate regression analyses showed that frailty, age, number of oral medicine, and history of myocardial infarction (MI) had significant correlations with PAD. Multivariate logistic regression analysis demonstrated that the factors independently associated with PAD were as follows: frailty (OR = 2.061, 95% C.I. 1.091-3.894) and MI (OR = 3.742, 95% C.I. 2.051-6.831). Conclusion: PAD is associated with frailty in HD patients.

Objective: Chronic angiotensin II (AngII) infusion promotes both thoracic (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Vasohibin-2 (VASH2) is known to cause angiogenesis at the sprouting front of neovascularization. The purpose of this study was to examine whether VASH2 influenced AngII-induced TAAs. Methods: Male C57BL/6J mice (10-week-old) were injected with VASH2 or LacZ expressing adenovirus (Ad; 7.5 x 10 9 vp/100 μL) via tail vein at 2 week intervals. One week after the first injection, subcutaneous infusion of either AngII (1,000 ng/kg/min) or saline by mini osmotic pumps was started for 3 weeks. Consequently, mice were divided into 4 groups: AngII + Ad VASH2 (n=22), AngII + Ad LacZ (n=21), saline + Ad VASH2 (n=10), saline + Ad LacZ (n=8). Next, in order to examine whether VASH2 affected TAAs via VEGF regulation, bevacizumab was intraperitoneally administrated into mice; AngII + Ad VASH2 + saline (n=15), AngII + Ad VASH2 + bevacizumab (n=15). TAAs were evaluated in all mice by en face method. Third, human aortic smooth muscle cells (hSMCs) were infected with Ad VASH2 or Ad LacZ, stimulated with or without AngII to evaluate further mechanism. Result: Intima area of aortic arch was significantly larger in AngII + Ad VASH2 group than in AngII + Ad LacZ group (19.78 ± 0.40 mm 3 vs 17.74 ± 0.44 mm 3 , P < 0.001). Gelatin zymography demonstrated that AngII upregulated latent MMP-2 expression, and activated MMP-2 most prominently in AngII + VASH2 group. Protein expression of p21 and p53 in thoracic aortas was enhanced in AngII + VASH2 group. Positive TUNEL staining was observed in thoracic aortic wall of AngII + VASH2 group. No significant difference in intima area of aortic arch between AngII + Ad VASH2 + saline group and AngII + Ad VASH2 + bevacizumab group. In vitro, the same results were observed regarding protein expression of p21 and p53, and TUNEL staining. In addition, Annexin-V staining was detected only in AngII + VASH2 group. Conclusion: Overexpression of VASH2 accelerated development of AngII-induced TAAs in vivo. VASH2-induced cell apoptosis may influence AngII-induced TAA formation independent of VEGF.

The population undergoing dialysis is aging worldwide, particularly in Japan. The clinical condition of frailty is the most problematic expression in the elderly population. Potential pathophysiological factors of frailty present in patients with CKD and are accentuated in patients with ESRD. The aim of this study was to identify the prevalence and predictors of frailty in Japanese HD patients. This study was a multicenter, cross-sectional and observational investigation conducted at 6 institutions. To evaluate frailty, the modified Fried's frailty phenotype adjusted for Japanese as the self-reported questionnaire was used. Of the 542 patients visiting each institution, 388 were enrolled in this study. In total, 26.0% of participants were categorized as not-frailty, 52.6% as pre-frailty and 21.4% as frailty. The prevalence of frailty increased steadily with age and was more prevalent in females than in males and the subjects with frailty received polypharmacy. A multivariate logistic regression analysis revealed that the factors independently associated with frailty were the following: female gender (odds ratio [OR] = 3.661, 95% confidence interval [CI] 1.398-9.588), age (OR = 1.065, 95% CI 1.014-1.119), age ≥ 75 years old (OR = 4.892, 95% CI 1.715-13.955), body mass index (BMI) < 18.5 (OR = 0.110, 95% CI 0.0293-0.416), number of medications being taken (OR = 1.351, 95% CI 1.163-1.570), diabetes mellitus (DM) (OR = 2.765, 95% CI 1.081-7.071) and MNA-SF ≤ 11 (OR = 7.405, 95% CI 2.732-20.072). Frailty was associated with the accumulation of risk factors. The prevalence of frailty in Japanese patients with HD was relatively lower than that previously reported in Western developed countries; however, it was extremely high compared to the general population regardless of age. Our findings suggest that frailty might be associated with an increase in the prevalence of adverse health outcomes in patients with HD.

Olmesartan and azilsartan, angiotensin II receptor blockers (ARBs), are expected to decrease blood pressure more than the other ARBs. We conducted randomized-controlled trials to compare the practical efficacy of olmesartan with azilsartan.Eighty-four patients treated with the conventional ARBs for more than 3 months were assigned randomly to receive either 20 mg of olmesartan (olmesartan medoxomil, OL group) or 20 mg of azilsartan (azilsartan, not azilsartan medoxomil, AZ group) once daily for 16 weeks. The practical efficacy on blood pressure was compared between the OL and AZ groups.Office blood pressure of both groups decreased significantly (OL group: 152/86-141/79 mmHg, P0.05, AZ group: 149/83-135/75 mmHg; P0.05). Diastolic home blood pressure in the AZ group decreased significantly (79±9-74±7 mmHg; P0.05), but not in the OL group (79±11-75±10 mmHg; P=0.068). However, there were no significant differences between the groups. The dosage of olmesartan and azilsartan increased significantly and slightly for 16 weeks (OL group: 20.3-23.1 mg; P0.05, AZ group: 20.5-23.2 mg; P0.05), without a significant difference between groups. Furthermore, there were no significant differences in renal function, lipid profiles, brain natriuretic peptide, soluble fms-like tyrosine kinase-1, and urinary L-type fatty acid-binding protein between the two groups.Both olmesartan and azilsartan equally reduced blood pressures. Both olmesartan and azilsartan showed a renoprotective effect and were well tolerated without any major adverse events.

Background: Cilostazol, a phosphodiesterase-3 inhibitor, plays vasoprotective roles such as an improvement of endothelial function, a vasodilatation and a suppression of proliferation of vascular smooth muscle cells. The aim of study was to investigate a cardioprotective effect of cilostazol. Method: Male apolipoprotein E deficient mice (8-12 weeks old) were fed with either normal chow diet or cilostazol-containing (0.1% wt/v) diet. After 1 week of cilostazol administration, mice were infused subcutaneously with either angiotensin II (AngII, 1,000 ng/kg/min, n = 16 - 19) or saline (n = 5 - 6) by osmotic minipumps for 4 weeks. Results: AngII equivalently increased systolic blood pressure, irrespective of cilostazol administration. Cilostazol had no effect on serum cholesterol concentrations, triglycerides, high-density lipoprotein-cholesterol, body weights, heart rates, and systolic blood pressures. AngII increased heart weight but was attenuated by cilostazol administration (6.7±0.8 to 6.0±0.7 mg/gBW, p < 0.05). Cilostazol prevented both perivascular and interstitial cardiac fibrosis induced by AngII (p < 0.05, each). Quantitative real-time PCR revealed that mRNA expressions of Ctgf , Collagen I , Collagen III , Tgf- , Hgf and Spp-1 increased by AngII infusion but were attenuated by cilostazol administration (p < 0.05). Immunohistochemical analysis demonstrated that AngII administration enhanced OPN expression in heart but was suppressed by cilostazol administration. Further, to investigate the mechanism, human cardiac myocytes were cultured and stimulated with AngII (1x10 -7 M). Co-treatment of Cilostazol (1x10 -7 to 1x10 -5 M) attenuated AngII-induced increase of Spp-1 gene expression in dose-dependent manner. This effect was mimic by a treatment with forskolin, which was diminished by co-treatment with H-89. Conclusion: Cilostazol attenuated AngII-induced cardiac fibrosis in vivo. Cilostazol attenuated AngII-induced increment of Spp-1 gene expression through cAMP-PKA dependent pathway.

Objective: Abdominal aortic aneurysm (AAA) is the most common aortic aneurysm. Chronic kidney disease (CKD) and diabetes mellitus (DM) are considered as risk factors for cardiovascular diseases. However, the association between CKD and AAA remains unknown. Although DM has been reported to exert protective effect on the incidence and development of AAA in western population, such protective role of DM was not explored in the Asian population. The purpose of this study was to determine the relationship of CKD and DM and the presence of AAA. We performed a cross-sectional retrospective case-control study in Asian population. Methods and Results: We enrolled 261 patients with AAA (AAA+) and age-and-sex matched 261 patients without AAA (AAA-) at two hospitals between 2008 and 2014, and examined the association between the risk factors and the presence of AAA. Furthermore, to investigate AAA prevalencein each group, we enrolled 1126 patients with CKD and 400 patients with DM. The presence of CKD in patients with AAA+ was significantly higher than that in patients with AAA- (AAA+; 65 %, AAA-; 52 %, P = 0.004). The presence of DM in patients with AAA+ was significantly lower than that in patients with AAA- (AAA+; 17 %, AAA-; 35 %, P < 0.001). A multivariate logistic regression analysis demonstrated that hypertension, ischemic heart disease and CKD were independent determinants, whereas, DM was the only independent protective factor, for the presence of AAA. The prevalence of AAA in patients with CKD 65 years old and above was 5.1 %, whereas, that in patients with DM 65 years old and above was only 0.6 %. Conclusion: CKD is a positively associated with the presence of AAA. In contrast, DM is a negatively associated with the presence of AAA.

Objective: Chronic angiotensin II (AngII) infusion promotes development of abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Previous studies have shown that local inflammation and increased oxidative stress plays an important role on formation of AAAs. In addition, voltage-dependent N-type Ca 2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by AngII in mice. Last year, we reported that cilnidipine, an N/L-type calcium channel blocker, attenuated AngII-induced AAAs in apolipoprotein E deficient mice. The purposed of this study was to determine the mechanism of cilnidipine reducing AngII-induced AAAs Methods and Results: Male apolipoprotein E deficient mice (8-12 weeks old) were fed a normal laboratory diet. Mice were infused subcutaneously with either cilnidipine or vehicle by osmotic minipumps. Three days later, mice were also infused subcutaneously with either AngII (1,000 ng/kg/min, n = 14-16) or saline (n = 4) by osmotic minipumps for 4 weeks. AngII increased systolic blood pressure. Cilnidipine decreased blood pressure in AngII-infused mice, but had not effect during saline infusion. Cilnidipine mildly restored plasma renin activity that were suppressed by AngII infusion. Cilnidipine mildly decreased plasma aldosterone concentrations that were increased by AngII infusion. Cilnidipine significantly reduced the incidence of AngII-induced AAAs (cilnidipine: 38 %, Vehicle: 88 %; P < 0.05). Elastica van Gieson staining demonstrated degeneration of elastic lamina by AngII was suppressed by cilnidipine administration. Immunohistochemical staining of CD68 revealed that cilnidipine administration attenuated accumulation of CD68 positive macrophage by AngII. In addition, cilnidipine reduced oxidative stress by AngII in 8-hydroxy-2’-deoxyguanosine and 4-Hydroxy-2-nonenal staining. Conclusion: Cilnidipine attenuated AngII-induced AAAs in male apolipoprotein E deficient mice by its anti-inflammation and anti-oxidative stress effect.

Objective: Chronic angiotensin II (AngII) infusion promotes both ascending (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Previous studies demonstrated that vascular endothelial growth factor (VEGF) enhanced AngII-induced AAA formation, and VEGF significantly increased AngII-induced AAA diameter in hypercholesterolemic mice. Vasohibin-1 (VASH-1) is induced by VEGF and inhibits angiogenesis at the termination zone under various pathologic conditions such as those of tumors, arterial intimal thickening and retinal neovasucularization. In contrast, a VASH-1 homolog, Vasohibin-2 (VASH-2), promotes angiogenesis at the sprouting front. Therefore, we hypothesized that exogenous VASH-2 influences AngII-induced TAAs in normocholesterolemic mice. The purpose of this study was to examine whether VASH-2 influenced AngII-induced TAAs. Methods and Results: Male C57BL/6J mice (10 weeks old) were fed a normal laboratory diet. Mice were injected 10^9 plaque-forming unit VASH-2 or Lac Z expressing adenovirus (Ad) via tail vein every other week. They were also infused subcutaneously with either AngII (1,000 ng/kg/min) or saline by osmotic mini-pumps for 3 weeks. The study mice had 4 groups: AngII + Ad VASH-2 (n=23), AngII + Ad Lac Z (n=23), Saline + Ad VASH-2 (n=13), Saline + Ad Lac Z (n=9). There were no significant differences between 4 groups in body weight. Plasma total cholesterol and VEGF concentrations were significantly increased in AngII infused groups (P < 0.05). Mortality ratio was 8.7% in AngII + Ad VASH-2 group and 4.3% in AngII + Ad Lac Z group. Intima area of aortic arch was significantly larger in AngII + Ad VASH-2 group than in AngII + Ad Lac Z group (19.78 ± 0.40 mm^3 vs 17.70 ± 0.41 mm^3, P < 0.01). AngII infusion significantly increased ex vivo maximal diameters of abdominal aorta, but there was no significant difference between VASH-2- and Lac Z-injected mice. Conclusion: Exogenous VASH-2 exacerbated AngII-induced ascending aortic aneurysms in male C57BL/6 mice.

Objective: Chronic infusion of angiotensin II (AngII) promotes development of abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Previous studies have shown that local inflammation and increased oxidative stress plays an important role on formation of AAAs. In addition, it is reported that voltage-dependent N-type Ca2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by AngII in mice. Therefore, we hypothesized that cilnidipine, an N/L-type calcium channel blocker, exerts vasoprotective effect by inhibiting inflammation and superoxide generation in mice. The purpose of this study was to evaluate whether cilnidipine influenced AngII-induced AAAs. Methods and Results: Male apolipoprotein E deficient mice (8-12 weeks old) were fed a normal laboratory diet. Mice were infused subcutaneously with either cilnidipine or vehicle by osmotic minipumps. Three days later, mice were also infused subcutaneously with either AngII (1,000 ng/kg/min, n = 14-16) or saline (n = 4) each by osmotic minipumps for 4 weeks. AngII increased systolic blood pressure. Cilnidipine decreased blood pressure in AngII-infused mice, but had not effect during saline infusion. AngII infusion did not alter serum cholesterol concentrations. However, cilnidipine slightly decreased serumcholesterol concentrations in AngII-infused mice. Cilnidipine had no effect on body weights, heart rates, and urine total protein, but mildly restored plasma renin activity that were suppressed by AngII infusion. Cilnidipine did not affect ex vivo measurement of maximal diameter of abdominal aorta (1.04 ± 0.09 mm vs 1.11 ± 0.06 mm, n.s.) in saline infused mice. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas, but was attenuated by cilnidipine (1.79 ± 0.59 mm vs 1.26 ± 0.38 mm, P < 0.05). In addition, cilnidipine significantly reduced the incidence of AngII-induced AAAs (Cilnidipine: 38 %, Vehicle: 88 %; P < 0.05). Furthermore, gelatin zymography demonstrated that cilnidipine diminished AngII-induced increase in aortic MMP-9 protein abundance. Conclusion: Cilnidipine attenuated AngII-induced AAAs in male apolipoprotein E deficient mice.

It has been reported that cyclosporine A (CsA) treatment may be associated with posterior reversible encephalopathy syndrome. We report a 16-year-old man who exhibited nephrotic syndrome and posterior reversible encephalopathy syndrome. Intensive antihypertensive therapy restored him to consciousness. Renal biopsy revealed that he suffered from focal segmental glomerulosclerosis. Although he was treated with prednisolone and low-density lipoprotein apheresis therapy, his proteinuria remained at high level. Then, mycophenolate mofetil (MMF) with less influence on vessel endothelium compared with CsA and tacrolimus was administered. Soon after, he reached remission of nephrotic syndrome without recurrence of posterior reversible encephalopathy syndrome. This is the first case that a young patient of focal segmental glomerulosclerosis with posterior reversible encephalopathy syndrome achieved a complete remission by MMF treatment without recurrence of posterior reversible encephalopathy syndrome. MMF may be effective for young patients of focal segmental glomerulosclerosis especially with clinical condition of vascular endothelial damage such as posterior reversible encephalopathy syndrome.

Objective: Previously, we demonstrated that cilostazol, a phosphodiesterase-3 inhibitor, attenuated AngII-induced abdominal aortic aneurysms (AAAs) in male apolipoprotein E (apoE) deficient mice. However, the mechanism of this protective effect is unknown. The purpose of this study was to elucidate the effect of cilostazol on inflammation and MMPs in several cell types present in AAAs. Methods and Results: First, aortic endothelial cells (ECs) were isolated from male apoE deficient mice. After confluence from 3 to 5 passages, ECs were incubated with saline, TNF-alpha, or TNF-alpha/cilostazol for 24 hours. Many inflammatory genes, such as MCP-1, IL-1beta, COX-2, ICAM-1 and VCAM-1, were increased by TNF-alpha, but the enhancements of them were attenuated by co-treatment of cilostazol. Western blot revealed that cilostazol attenuated TNF-alpha-induced ICAM-1 protein expression. Second, aortic vascular smooth muscle cells (VSMCs) were isolated from male apoE deficient mice. Cultured VSMCs were incubated with saline, TNF-alpha, or TNF-alpha/cilostazol for 24 hours. Similar to ECs, cilostazol decreased gene expression of inflammation such as MCP-1, COX-2, iNOS, OPN, and gene expression of MMP-2 and -9 that were induced by TNF-alpha. Third, we harvested peritoneal macrophages from male apoE deficient mice. 24 hours incubation with TNF-alpha induced MMP-2 and MMP-9 gene expression. Co-treatment with cilostazol attenuated gene expression of these proteases. Conclusion: Our results indicate that cilostazol exerts anti-inflammatory effect on selected cell types that promote arterial vascular wall inflammation. This effect might, in part, contribute to attenuated AngII-induced AAAs in male apoE deficient mice.

Objective: Chronic infusion of angiotensin II (AngII) augments the development of abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Several studies have suggested that intercellular adhesion molecule 1 (ICAM-1) expression increases in association with AAA formation. The aim of the study was to define whether ICAM deficiency influenced AngII-induced AAA formation. Methods and Results: Apolipoprotein E deficient (apoE -/-) mice were cross-bred with ICAM-1 deficient mice. Male apoE -/- mice fed a normal diet and infused subcutaneously with saline or AngII (1,000 ng/kg/min) via osmotic mini pump for 1 week. AngII infusion increased aortic ICAM-1 protein. Male apoE -/- mice that were either ICAM-1 +/+ or -/- were fed a normal diet and infused subcutaneously with AngII (1,000 ng/kg/min) via osmotic mini pump for 4 weeks. Total ICAM-1 deficiency had no significant effect on body weight, total cholesterol concentrations, or systolic blood pressures prior to and during AngII infusion. AngII induced expansion of ex vivo maximal diameters of abdominal aortas was attenuated significantly in ICAM-1 deficient mice (ICAM-1 +/+, 1.78 ± 0.20 mm; ICAM-1 -/-, 1.07 ± 0.03 mm, P < 0.0001). ICAM-1 deficiency also reduced significantly the incidence of AngII-induced AAAs (ICAM-1 +/+, 76%; ICAM-1 -/-, 13%, P < 0.0001). Furthermore, bone-marrow transplantation was performed to develop chimeric mice that were ICAM-1 +/+ or -/- in donor cells and ICAM-1 +/+ or -/- in recipient cells. ICAM-1 deficiency in either donor or recipient cells had no effect on body weight, total cholesterol concentrations, or systolic blood pressure. Recipient ICAM-1 deficiency significantly attenuated the incidence of AngII-induced AAA formation (ICAM-1 +/+, 67%; ICAM-1 -/-, 19%, P = 0.0008). Furthermore, lack of ICAM-1 reduced AngII-induced aortic MMP-2 activation (P < 0.05). Conclusion: ICAM-1 deficiency attenuated AngII-induced AAAs in male apoE -/- mice.

A 71-year-old woman presented with a high-grade fever, neck pain, anemia and thrombocytopenia. After performing further examinations, we concluded that she had simultaneously developed large vessel vasculitis and myelodysplastic syndrome (MDS). Although glucocorticoid administration improved her clinical symptoms, the MDS transformed into acute myeloid leukemia and she died one year after receiving the diagnosis. The occurrence of immune-mediated disorders in patients with MDS is a well-known phenomenon; however, large vessel vasculitis is a rare complication of MDS. Our case suggests that the association between systemic vasculitis and MDS may result in poor outcomes.

Objective Chronic angiotensin II (AngII) infusion promotes development of abdominal aortic aneurysms (AAAs) in mice. Previous studies have shown that local inflammation plays an important role on formation of AAAs. Cilostazol, a phosphodiesterase-3 inhibitor with antiplatelet aggregation and vasodilatory effects, exerts vasoprotective effect by inhibiting inflammation and superoxide generation in several experimental studies. The purpose of this study was to evaluate whether cilostazol influenced AngII-induced AAAs. Methods and Results Male apolipoprotein E deficient mice (8-12 weeks old) were fed with either normal diet or cilostazol-containing (0.1% wt/v) diet. After 1 week of cilostazol administration, mice were infused subcutaneously with either AngII (1,000 ng/kg/min, n = 16 -19) or saline (n = 5 - 6) by osmotic minipumps for 4 weeks. AngII equivalently increased systolic blood pressure, irrespective of cilostazol administration. Cilostazol had no effect on serum cholesterol concentrations, triglycerides, high-density lipoprotein-cholesterol, body weights, heart rates, and systolic blood pressures. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas that were attenuated by cilostazol administration (1.94 ± 0.16 mm vs 1.53 ± 0.17 mm, P < 0.05). Cilostazol diminished AngII-induced increase of aortic MMP-2 activity and ICAM-1 protein expression as determined by gelatin zymography and Western blot, respectively (P < 0.05, each). Aortic mRNA expression of inflammatory cytokines such as MCP-1, IL-1β, osteopontin, and COX-2 was reduced by cilostazol administration (P < 0.05). In vitro, TNF-α increased MCP-1, ICAM-1 and VCAM-1 mRNA expression in mouse aortic endothelial cells. These enhancements were decreased by incubation with cilostazol (P < 0.05). Conclusion Cilostazol attenuated AngII-induced AAAs thorough its anti-inflammatory effect in male apolipoprotein E deficient mice.

Objective: Chronic infusion of angiotensin II (AngII) promotes development of abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Previous studies have shown that local inflammation and increased oxidative stress plays an important role on formation of AAAs. Cilostazol, a phosphodiesterase-3 inhibitor with antiplatelet aggregation and vasodilatory effects, exerts vasoprotective effect by inhibiting inflammation and superoxide generation in several experimental studies. The purpose of this study was to evaluate whether cilostazol influenced AngII-induced AAAs. Methods and Results: Male apolipoprotein E deficient mice (8-12 weeks old) were fed with either normal diet or cilostazol-containing (0.1% wt/v) diet. After 1 week of cilostazol administration, mice were infused subcutaneously with either AngII (1,000 ng/kg/min, n = 16 -18) or saline (n = 5 - 6) by osmotic minipumps for 4 weeks. AngII equivalently increased systolic blood pressure, irrespective of cilostazol adminstration. Cilostazol had no effect on serum cholesterol concentrations, triglycerides, high-density lipoprotein-cholesterol, body weights, heart rates, and systolic blood pressures. Cilostazol did not affect ex vivo measurement of maximal diameter of abdominal aorta (0.88 ± 0.04 mm vs 0.88 ± 0.03 mm, n.s.) in saline infused-mice. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas but cilostazol administration attenuated (1.94 ± 0.16 mm vs 1.53 ± 0.17 mm, P < 0.05). In addition, gelatin zymography demonstrated that cilostazol diminished AngII-induced increase in aortic MMP-2 activity (P < 0.05). Conclusion: Cilostazol attenuated AngII-induced AAAs in male apolipoprotein E deficient mice.

Background A link between IgA nephropathy and Crohn’s disease has recently been reported. Other researchers hypothesize that intestine-derived IgA complexes deposit in glomerular mesangial cells, eliciting IgA nephropathy. Intestinal mucosal plasma cells mainly secrete IgA2. Nevertheless, IgA1 deposition is strongly implicated as being the primary cause of IgA nephropathy. Case presentation A 46-year-old Japanese man developed IgA nephropathy 29 years ago, following tonsillectomy. As a result, a normal urinalysis was obtained. The patient previously suffered Crohn’s disease followed by urinary occult blood and proteinuria six years ago. Exacerbation of IgA nephropathy was highly suspected. Therefore a renal biopsy was performed. A diagnosis of exacerbation of IgA nephropathy with mesangial cell proliferation and fibrotic cellular crescent was based upon the pathological findings. The patient exhibited a positive clinical course and eventually achieved a remission with immunosuppressive therapy including prednisolone treatment. Immunostaining for the detection of IgA subtypes was performed on both of his kidney and excised ileum. The results revealed IgA1 and IgA2 deposition by submucosal cells in intestine. Furthermore, IgA1 deposition of mesangial areas in the patient’s kidney, indicated an association of IgA1 with the exacerbation of IgA nephropathy. Conclusion This case represents the possibility that the intestine-derived IgA1 can be the origin of galactose-deficient IgA which is known to cause IgA nephropathy exacerbation.