Haruhisa Otani

Effects of Coffee Consumption on Oxidative Susceptibility of Low-Density Lipoproteins and Serum Lipid Levels in Humans

Since little is known about how coffee intake affects low-density lipoprotein (LDL) oxidative susceptibility and serum lipid levels, we conducted anin vivo study in 11 healthy male students of Wakayama Medical University aged between 20 and 31 years fed an average Japanese diet. On days 1-7 of the study, the subjects drank mineral water. On day 7, the subjects began drinking coffee, 24 g total per day, for one week. This was followed by a one week “washout period” during which mineral water was consumed. Fasting peripheral venous blood samples were taken at the end of each one-week period. LDL oxidation lag time was approximately 8% greater (p < 0.01) after the coffee drinking period than the other periods. Serum levels of total cholesterol and LDL-cholesterol (LDL-C) and malondialdehyde (MDA) as thiobarbituric acid reactive substances (TBARS) were significantly decreased after the coffee drinking period. Finally, regular coffee ingestion may favorably affect cardiovascular risk status by modestly reducing LDL oxidation susceptibility and decreasing LDL-cholesterol and MDA levels.

Effect of vitamin E on lipid metabolism and atherosclerosis in ESRD patients

BACKGROUND Oxidative stress is enhanced in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). Bioincompatibility represents an important source of reactive oxygen species. HD patients exhibit altered anti-oxidative defences and anti-oxidative vitamins such as vitamin E and C are altered in uremia. Frequently, HD patients also suffer from atherosclerotic cardiac disease. We have previously reported that low density lipoprotein (LDL) of HD patients is rich in malondialdehyde (MDA), an end product of lipid peroxidation. MDA rich LDL is thought to be an atherogenic lipoprotein due to its enhancement of macrophage foam cell formation. METHODS We conducted a controlled study for two years comparing the effects of a vitamin E coated cellulose membrane dialyzer and an ordinary cellulose membrane dialyzer on lipid metabolism and the progress of atherosclerosis. LDL-MDA and oxidized LDL (ox-LDL) were measured in HD patients using these two types of dialyzers. Plasma vitamin E and lipid concentrations were also evaluated. The aortic calcification index (ACI) was evaluated by CT scan to assess the progress of atherosclerosis before and for every year after treatment. RESULTS Use of a vitamin E coated cellulose membrane dialyzer for six months, one year and two years resulted in a significant reduction in LDL-MDA and ox-LDL compared to the ordinary cellulose membrane dialyzer. Treatment with a vitamin E-coated dialyzer significantly reduced the percentage increase in ACI after 24 months compared to the control. There were no significant changes in plasma vitamin E and lipid concentrations between the two groups. CONCLUSIONS These results suggest that the oxidative stress could be one of the stimulating factors of abnormal lipid metabolism and atherosclerosis in ESRD patients.

Deletion of the kinase domain in death-associated protein kinase attenuates tubular cell apoptosis in renal ischemia-reperfusion injury

Death-associated protein kinase (DAPK) is a calcium/calmodulin-dependent serine/threonine kinase localized to renal tubular epithelial cells. To elucidate the contribution of DAPK activity to apoptosis in renal ischemia-reperfusion (IR) injury, wild-type (WT) mice and DAPK-mutant mice, which express a DAPK deletion mutant that lacks a portion of the kinase domain, were subjected to renal pedicle clamping and reperfusion. After IR, DAPK activity was elevated in WT kidneys but not in mutant kidneys (1785.7 +/- 54.1 pmol/min/mg versus 160.7 +/- 60.6 pmol/min/mg). Furthermore, there were more TUNEL-positive nuclei and activated caspase 3-positive cells in WT kidneys than in mutant kidneys after IR (24.0 +/- 5.9 nuclei or 9.4 +/- 0.6 cells per high-power field [HPF] versus 6.3 +/- 2.2 nuclei or 4.4 +/- 0.7 cells/HPF at 40 h after ischemia). In addition, the increase in p53-positive tubule cells after IR was greater in WT kidney than in mutant kidneys (9.9 +/- 1.4 cells/HPF versus 0.8 +/- 0.4 cells/HPF), which is consistent with the theory that DAPK activity stabilizes p53 protein. Finally, serum creatinine levels after IR were higher in WT mice than in mutant mice (2.54 +/- 0.34 mg/dl versus 0.87 +/- 0.24 mg/dl at 40 h after ischemia). Thus, these results indicate that deletion of the kinase domain from DAPK molecule can attenuate tubular cell apoptosis and renal dysfunction after IR injury.

Effect of environmental changes on oxidative deoxyribonucleic acid (DNA) damage in systemic lupus erythematosus

Abstract In a study conducted in Japan, the authors used urinary 8-hydroxydeoxyguanosine (8-OHdG) to study the effects of high-intensity and low-intensity sunlight on oxidative damage to deoxyribonucleic acid (DNA) in patients who had systemic lupus erythematosus (SLE). During late May through early September (i.e., a period of high-intensity sunlight), the mean urinary 8-OHdG level in SLE patients was significantly higher than in controls (31.0 ± 20.6 [standard deviation] ng/mg vs. 15.4 ± 7.2 ng/mg, respectively [p < .05]). During late November through early March (i.e., low-intensity sunlight season), however, no significant differences were noted (15.4 ± 5.5 ng/mg vs. 16.3 ± 4.6 ng/mg, respectively). The mean urinary 8-OHdG level in SLE patients during the period of high-intensity sunlight was significantly higher than during the period of low-intensity sunlight (21.3 ± 20.6 ng/mg vs. 12.6 ± 6.7 ng/mg, respectively; p < .01), although no such seasonal changes were observed among controls (16.2 ± 8.0 ng/mg vs. 15.7 ± 5.1 ng/mg, respectively). The effect of sunlight intensity (i.e., season) may require consideration when oxidative DNA damage occurs in individuals who have SLE.

Tonsillectomy with steroid pulse therapy has more effect on the relapse rate than steroid pulse monotherapy in IgA nephropathy patients.

AIMS Both steroid pulse (SP) monotherapy and the combination of tonsillectomy and SP therapy (TSP) are effective for achieving clinical remission (CR), defined as negative hematuria and proteinuria, in patients with IgA nephropathy (IgAN). The role of tonsillectomy in the treatment of IgAN has been analyzed only from the aspect of CR or renal survival after TSP treatment, so there is no evidence of its effect on the relapse after CR. METHODS We retrospectively investigated relapse (re-appearance of urinary abnormalities) from CR after TSP or SP monotherapy in 62 IgAN patients (mean follow-up, 70.1 ± 35.3 months). The SP therapy comprised 0.5 g methylprednisolone administered intravenously on 3 consecutive days followed by oral prednisolone (30 mg/day) on 4 consecutive days, with the course repeated 3 times. Oral prednisolone (30 mg/day) was then given on alternative days and gradually tapered and finished over 1 year. Tonsillectomy was performed either before or within 6 months of starting SP therapy. RESULTS At baseline, the mean age was 34.6 years, the mean serum creatinine (Cr) level was 0.9 mg/dl, and the mean level of proteinuria was 876 mg/day. There were no differences between the TSP group (41 patients) and SP monotherapy group (21 patients). In total, 24 of the TSP and 10 of the SP patients achieved CR. Of the 34 patients who achieved CR, 13 relapsed after TSP or SP monotherapy. Using Kaplan-Meier analysis, tonsillectomy was associated with a lower incidence of relapse from CR after treatment (p = 0.045). Multivariate Cox regression analysis revealed that tonsillectomy reduced the rate of from CR after SP therapy. CONCLUSION Tonsillectomy was associated with a reduction in the relapse rate from CR after SP therapy in IgAN patients.

Effects of antioxidants on kidney disease.

Kidney mesangial cells (MCs) and vascular smooth muscle cells (VSMCs) are closely related in terms of origin, microscopic anatomy, histochemistry, and contractility. This relationship suggests a similarity between kidney glomerular sclerosis and atherosclerosis. Vitamin E appears beneficial in the prevention and treatment of coronary disease and also inhibits the proliferation of VSMCs in vitro. We used vitamin E and probucol to treat glomerular sclerosis and MC-proliferative glomerulonephritis (GN) in two animal models of glomerular disease. Using rats, a remnant kidney model accelerated with hyperlipidemia was employed to reflect progressive glomerular sclerosis leading to chronic renal failure, and an anti-thymocyte serum treatment was used to model acute MC-proliferative GN. Supplemental dietary antioxidants suppress MC proliferation and glomerular sclerosis in models of glomerular disease in rats. These results suggest that treatment with antioxidants may be a promising intervention to prevent progression of kidney disease.

Involvement of MCP-1 and M-CSF in glomerular foam cell formation in ExHC rats

BACKGROUND An increase in glomerular macrophages (MO) is considered a potential effector mechanism by which hypercholesterolemia exacerbates glomerular injury. To investigate the mechanism underlying recruitment of MO into glomeruli, the expression of glomerular monocyte chemoattractant protein-1 (MCP-1) and macrophage colony-stimulating factor (M-CSF) mRNA were examined using a lipid-induced glomerular injury rat model. METHODS Eight-week-old male ExHC rats, a strain susceptible to hyperlipidemia, were divided into the following 4 groups: a control group (C), a high cholesterol diet group (HH), a high cholesterol diet/standard diet group (HN), which were fed a high cholesterol diet for the first 4 weeks and a standard diet for the following 4 weeks, and a probucol-treatment group (PT). Both MCP-1 and M-CSF mRNA expression in glomeruli were analyzed using the RT-PCR method. An additional experimental group (M) fed a high cholesterol diet was administered M-CSF daily for 4 weeks. RESULTS The expression of MCP-1 mRNA in glomeruli increased accompanied by an increased total serum cholesterol level in HH and HN. However, M-CSF mRNA expression was significantly suppressed at 1 or 2 weeks and gradually increased to almost basal levels. In the PT group, MCP-1 mRNA expression was suppressed. The early suppression of M-CSF mRNA expression was inhibited in PT. Renal histology showed a significant increase in foam cells in glomeruli in HH and HN rats at 4 weeks. HH rats showed increased and expanded foam cells at 8 weeks. In HN rats, however, foam cells decreased significantly after the transfer to a standard diet from a high cholesterol diet. The MCP-1 mRNA expression was suppressed after the transfer. In the PT group, foam cell formation was also suppressed. Foam cells were identified as MO. M-CSF-treatment significantly suppressed foam cell formation in glomeruli when compared with the untreated group levels. CONCLUSION These findings suggest that hypercholesterolemia stimulated the expression of MCP-1 in glomeruli and attracted the MO into glomeruli. They also suggest that the reduction of hypercholesterolemia after the change in diet or treatment with probucol suppressed glomerular injury by suppressing the glomerular MCP-1 expression. M-CSF may suppress the recruitment of MO into glomeruli and foam cell formation at an early stage of hypercholesterolemia-induced glomerular injury.

Various dietary protein intakes and progression of renal failure in spontaneously hypercholesterolemic Imai rats.

Background/Aim: Dietary protein restriction is known to be beneficial in the preservation of the renal function in patients with chronic renal failure. Recently, the effect of varying quantity and quality of dietary protein intakes was also studied. This study investigates the effects of different dietary animal proteins on renal function in spontaneously hypercholesterolemic Imai rats that exhibit renal lesions similar to human focal and segmental glomerulosclerosis. The sources of proteins were from casein, pork, and fish. Primary concern was the effect of fish meat protein, because the effects of fish oil are well reported. To examine whether remnants of fish oil affect the experimental results, semi-defatted fish meat and fully defatted fish meat were prepared for these experiments. Methods: Forty-two Imai rats were placed on diets containing casein, defatted pork meat, semi-defatted fish meat, or defatted fish meat as a protein sources from 10 to 22 weeks of age. Twenty-four hour urine collections were obtained along with measurements of systolic blood pressure and drawing blood from the tail artery every 4 weeks. Finally, the kidneys were removed and prepared for histological study. Results: The semi-defatted fish meat diet retarded the rise of plasma cholesterol, virtually completely prevented the development of hypertriglyceridemia, and slowed the progression of proteinuria, renal function failure, and glomerular injury as compared with the control casein diet. However, the fully defatted fish meat diet led to renal failure at the same rate as the casein diet. The defatted pork diet group exhibited a higher creatinine clearance at the end of the experiments as compared with the casein and the fully defatted fish meat diet groups. Conclusions: These data suggest that an important determinant of the protective effects of the semi-defatted fish meat diet was related to the prevention of hypercholesterolemia and hypertriglyceridemia by the remaining fish oil. Fish meat protein itself did not indicate superior beneficial effects in the regression of the renal function in Imai rats as compared with casein protein, and defatted pork showed better results than casein and fully defatted fish meat.

Abnormal lipid metabolism and oxidative stress in hemodialysis patients

Oxidative stress is enhanced in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). Bioincompatibility represents an important source of reactive oxygen species. HD patients exhibit altered antioxidative defenses, and antioxidative vitamins such as vitamin E and C are altered in uremia. Frequently, HD patients also suffer from atherosclerotic cardiac disease. We previously reported that low-density lipoprotein (LDL) of HD patients is rich in malondialdehyde (MDA), an end product of lipid peroxidation. MDA-rich LDL is thought to be an atherogenic lipoprotein because of its enhancement of macrophage foam-cell formation. We conducted a controlled study for 2 years comparing the effects of a vitamin E-coated cellulose membrane dialyzer and an ordinary cellulose membrane dialyzer on lipid metabolism and the progress of atherosclerosis. LDL MDA and oxidized LDL (ox-LDL) were measured in HD patients by using these two types of dialyzers. Plasma vitamin E and lipid concentrations were also evaluated. Aortic calcification index (ACI) was evaluated by CT scan to assess the progress of atherosclerosis before and every year after initiation of the treatment. The use of a vitamin E-coated cellulose membrane dialyzer for 6 months, 1 year, and 2 years resulted in a significant reduction in LDL-MDA and ox-LDL compared with that obtainal with the use of the ordinary cellulose membrane dialyzer. The treatment with a vitamin E-coated dialyzer significantly reduced the percent increase in ACI after 24 months as compared with control. There were no significant differences in plasma vitamin E and lipid concentrations between the two groups. These results suggest that oxidative stress could be one of the factors stimulating abnormal lipid metabolism and atherosclerosis in ESRD patients.Oxidative stress is enhanced in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). Bioincompatibility represents an important source of reactive oxygen species. HD patients exhibit altered antioxidative defenses, and antioxidative vitamins such as vitamin E and C are altered in uremia. Frequently, HD patients also suffer from atherosclerotic cardiac disease. We previously reported that low-density lipoprotein (LDL) of HD patients is rich in malondialdehyde (MDA), an end product of lipid peroxidation. MDA-rich LDL is thought to be an atherogenic lipoprotein because of its enhancement of macrophage foam-cell formation. We conducted a controlled study for 2 years comparing the effects of a vitamin E-coated cellulose membrane dialyzer and an ordinary cellulose membrane dialyzer on lipid metabolism and the progress of atherosclerosis. LDL MDA and oxidized LDL (ox-LDL) were measured in HD patients by using these two types of dialyzers. Plasma vitamin E and lipid concentrations were also evaluated. Aortic calcification index (ACI) was evaluated by CT scan to assess the progress of atherosclerosis before and every year after initiation of the treatment. The use of a vitamin E-coated cellulose membrane dialyzer for 6 months, 1 year, and 2 years resulted in a significant reduction in LDL-MDA and ox-LDL compared with that obtainal with the use of the ordinary cellulose membrane dialyzer. The treatment with a vitamin E-coated dialyzer significantly reduced the percent increase in ACI after 24 months as compared with control. There were no significant differences in plasma vitamin E and lipid concentrations between the two groups. These results suggest that oxidative stress could be one of the factors stimulating abnormal lipid metabolism and atherosclerosis in ESRD patients.

Behçet's disease complicated by IgA nephropathy and interstitial nephritis

A 46-year-old man presenting with pharyngodynia and fever was treated with non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics, without initial improvement. Conjunctival injection in the left eye appeared soon thereafter, followed by an ulcer on the glans penis 2 weeks later. On admission to our hospital, his urine was positive for protein and occult blood. Multiple folliculitis-like eruptions were noted over the lumbar region to the abdomen. Based on these mucocutaneous symptoms and a positive reaction for HLA-B51 antigen, a diagnosis of Behçets disease was made. Renal biopsy revealed IgA nephropathy and interstitial nephritis. Urinary and other symptoms were alleviated with continued anti-inflammatory therapy. A lymphocyte stimulation test was performed to determine whether there was any relationship of the interstitial nephritis to drugs used in his treatment (ciprofloxacin, cefazolin sodium, or the NSAIDs), but results were not conclusive. Behçets disease complicated by nephropathy, notably interstitial nephritis, is rare; this valuable experience is now reported.