Yuriko Yonekura

Anti-oxidative effect of AST-120 on kidney injury after myocardial infarction.

Chronic kidney disease (CKD) is a crucial risk factor for cardiovascular disease (CVD), and combined CKD and CVD further increases morbidity and mortality. Here, we investigated effects of AST‐120 on oxidative stress and kidney injury using a model of myocardial infarction (MI) in rats.

The Vitamin D Receptor Activator Maxacalcitol Provides Cardioprotective Effects in Diabetes Mellitus

PurposeRecent reports showed a significant association between vitamin D levels and cardiovascular disease events and mortality. In the current study, we investigated the effect of the vitamin D receptor activator maxacalcitol (OCT) on cardiac damage in a rat model of type 2 diabetes.MethodsAt 20 weeks of age, the rats were divided into three groups: vehicle-treated (DM), insulin-treated (INS) and OCT-treated (OCT). At 30 weeks, the rats were sacrificed and urinary and blood biochemical analyses and cardiac histological and immunohistochemical analyses were performed. To evaluate the effect of OCT on the renin-angiotensin system, we performed a further study using aliskiren (ALS). At 20 weeks, the diabetic rats were divided into two groups: the ALS-treated group (ALS) and the ALS plus OCT-treated group (ALS + OCT), and we evaluated the renin-angiotensin system (RAS) and cardiac lesions at 30 weeks.ResultsAt 30 weeks, despite comparable blood pressure and renal function, heart volume, intracardiac oxidative stress by immunohistological analysis, cardiac and perivascular fibrosis and urinary excretion of 8-hydroxydeoxyguanosine and serum N-terminal pro-brain natriuretic peptide levels were significantly decreased in the OCT group compared to the DM group. mRNA expressions of dihydronicotinamide adenine dinucleotide phosphate (NADPH) p47 subunit and cardiac injury-related markers in the heart were also significantly decreased in the OCT group compared to the DM group. The cardioprotective effect of OCT was preserved even in the context of RAS inhibition.ConclusionOur results suggest that OCT prevents the development of cardiac damage in DM, independent of RAS inhibition.

Riser pattern is a predictor of kidney mortality among patients with chronic kidney disease

ABSTRACT Background: Hypertension is a crucial risk factor for cardiovascular death and loss of residual kidney function. Absence of the nocturnal decline in blood pressure (BP) predicts cardiovascular events and poor prognosis. However, characteristics of hypertension in moderate-to-severe chronic kidney disease (CKD) have not been fully evaluated. We aimed to assess the circadian variation of BP and kidney survival in CKD patients. Methods: Patients who were examined by 24-h ambulatory BP monitoring (ABPM) and estimated glomerular filtration rate (eGFR), <45 ml/min/1.73 m2, were enrolled in the study. The impacts of BP circadian rhythm and brain natriuretic peptide (BNP) on kidney survival were evaluated. Results: A total of 124 patients were enrolled. The average age was 64 ± 14 years, 57% were male, and 43% had diabetes. Forty-five percent of patients had a non-dipper pattern, 35% had a riser pattern, 19% had a dipper pattern, and 1% had an extreme-dipper pattern. The prevalence of diabetes and plasma BNP levels was higher and eGFR was lower in the riser-pattern group than in the non-riser-pattern group. Kidney survival rates were significantly worse in the riser-pattern group than in the non-riser-pattern group (p < 0.05). Moreover, among riser and non-riser pattern groups divided by BNP levels, the riser group with higher BNP level showed the worst kidney survival (p < 0.05). Conclusion: The riser pattern is frequently associated with several conditions at higher risk for kidney survival. Patients with a rising pattern and higher BNP levels have a worse kidney prognosis.

Anti-oxidative effect of the β-blocker carvedilol on diabetic nephropathy in non-obese type 2 diabetic rats

Oxidative stress plays an important role in the pathogenesis of diabetic nephropathy. The β‐blocker carvedilol has been proven to have an anti‐oxidant property. The aim of the present study was to elucidate the effects of carvedilol on diabetic nephropathy. At 20 weeks of age, male Spontaneously Diabetic Torii (SDT) rats were divided into three groups based on treatment: (i) an INS group (administered insulin); (ii) a CAR group (administered 10 mg/kg per day, p.o., carvedilol); and (iii) a diabetic (DM) group (administered vehicle). Rats were treated for a period of 10 weeks and were killed at 30 weeks of age. Urinary albumin excretion, renal histomorphology, and oxidative stress were evaluated. Urinary albumin excretion was significantly lower in the CAR than DM group (42.82 ± 3.94 vs 76.62 ± 13.74 mg/day respectively; P < 0.05). The mesangial index was lower in the CAR group than in the DM group. Urinary excretion of 8‐hydroxydeoxyguanosine (8‐OHdG), the number of 8‐OHdG‐positive cells in glomeruli, and the mRNA expression of NADPH oxidase p22phox and p47phox were also lower in the CAR than DM group. However, haemoglobin A1c (HbA1c) and blood pressure levels were comparable between the two groups. The results suggest that carvedilol could prevent the progression of diabetic nephropathy by suppressing oxidative stress.

22-Oxacalcitriol attenuates bone loss in nonobese type 2 diabetes

Active vitamin D is a major therapeutic agent for bone disease. Although some studies have reported that vitamin D ameliorates bone disease related to diabetes, the mechanism remains unclear. Our study investigated the effect of the vitamin D receptor activator 22-oxacalcitriol (OCT) on bone disease in a rat model of diabetes. OCT was administered at a dose of 0.2μg/kg three times per week for 10weeks. We performed blood and urine analyses, single energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and oxidative stress assessment in rats at 30weeks of age. OCT did not affect hemoglobin A1c or serum calcium levels. Bone mineral density (BMD), bone volume in the cortical and trabecular bones, and bone turnover were decreased in rats with diabetes. OCT treatment increased BMD and bone formation and tended to increase bone volume in the trabecular bone, but did not change bone volume in the cortical bone or bone resorption. The urinary oxidative stress marker 8-hydroxydeoxyguanosine (8-OHdG) excretion and the number of 8-OHdG-positive cells in bone were increased in rats with diabetes, and OCT treatment suppressed these increases. Our data suggest that OCT attenuated bone loss in a rat model of diabetes. This attenuation may be partially mediated by improved bone formation resulting from the antioxidative effect of OCT.

Comparison of the effects of novel vitamin D receptor analog VS-105 and paricalcitol on chronic kidney disease-mineral bone disorder in an experimental model of chronic kidney disease

When using vitamin D, the most important clinical problems are hypercalcemia, hyperphosphatemia, and vascular calcification. VS-105 is a novel vitamin D receptor (VDR) analog. In the present study, we compared the effects of VS-105 and paricalcitol on chronic kidney disease-mineral bone disorder (CKD-MBD) in a CKD rat model. We used male Sprague-Dawley (SD) rats and performed 5/6 nephrectomy at 8-9 weeks. At 10 weeks, the rats were classified into five groups and administered vehicle, low-dose paricalcitol (LP, 0.1μg/kg), high-dose paricalcitol (HP, 0.3μg/kg), low-dose VS-105 (LV, 0.2μg/kg), and high-dose VS-105 (HV, 0.6 μg/kg) three times a week for 10 weeks. There were no significant differences in blood pressure or renal function among the five groups. Alhough serum calcium levels were comparable between the LP and LV groups, they were higher in the HP group than in the HV group. Serum phosphate levels were higher in the paricalcitol-treated groups than in the VS-105-treated groups and paticularly higher in the HP group than in the other groups. The urinary excretion of phosphate was greater in the VS-105-treated groups than in the paricalcitol-treated groups. Serum parathyroid hormone (PTH) levels decreased and serum fibroblast growth factor-23 (FGF23) levels were elevated after administering paricalcitol and VS-105; however, serum FGF23 levels were remarkably elevated in the paricalcitol-treated groups. Further biochemical analyses revealed that the calcium content of the aorta was higher in the paricalcitol-treated groups than in the VS-105-treated group. VDR and Klotho expression in the kidney was significantly higher in the VS-105-treated groups than in the paricalcitol-treated groups although both agents increased these expressions. Our data suggest that VS-105 had a lesser effect on CKD-MBD than paricalcitol except in the case of serum PTH levels. The mechanism appears to be associated with the difference in VDR and Klotho expression.