Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice.

Diabetic kidney disease (DKD) is among the most common and serious complications of both type 1 and type 2 diabetes. In this study, we used KK/Ta-Ins2Akita (KK-Akita) mice as a model of DKD and KK/Ta (KK) mice as controls to identify novel factors related to the development/progression of DKD. Capillary electrophoresis coupled with mass spectrometry analysis revealed that circulating Asp (l-aspartic acid) levels in diabetic KK-Akita mice tend to be lower than those in control KK mice. Therefore, we evaluated the effect of Asp supplementation to prevent the progression of DKD in KK-Akita mice. Mice were divided into three groups: (a) untreated KK mice (Control group), (b) untreated KK-Akita mice (DKD group), and (c) treated (double-volume Asp diet) KK-Akita mice (Tx group). Kidney sections were stained with fluorescein isothiocyanate-labeled lectins, wheat germ agglutinin (WGA), and anti-endothelial nitric oxide synthase (eNOS) antibody for evaluation of endothelial surface layer (ESL) and NO synthesis. The mesangial area and glomerular size in the DKD group were significantly larger than those in the Control group; however, there was no significant difference in those between the DKD and Tx groups. Albuminuria, the ratio of foot process effacement, and thickness of glomerular basement membrane in the Tx group were significantly lower than those in the DKD group. Furthermore, the expression levels of glomerular WGA and microvascular eNOS in the Tx group improved significantly and approached the level in the Control group. In conclusion, the improvement of albuminuria in the Tx group may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular ESL.

Effect of Zinc Acetate Dihydrate (NobelzinR) Treatment on Anemia and Taste Disorders in Patients with Chronic Kidney Disease with Hypozincemia.

Some patients with chronic kidney disease (CKD) receiving hemodialysis develop erythropoietin-resistant anemia, possibly due to zinc deficiency. The frequency of zinc deficiency in CKD (stages 1-5 and 5D) and CKD improvement via zinc supplementation are not completely verified. Here 500 CKD patients (Stage 1/2, n=100; Stage 3, n=100; Stage 4, n=100, Stage n=5, 100; Stage 5D, n=100) will be recruited to determine the frequency of serum zinc deficiency at each CKD stage. Patients with serum zinc concentrations <80 µg/dL will be treated with zinc acetate dihydrate (NobelzinR) to evaluate its effects on hypozincemia, taste disturbances, and anemia.

Pleiotropic effect of pyridoxamine on diabetic complications via CD36 expression in KK-Ay/Ta mice.

AIM: Pyridoxamine inhibits the development of diabetic complications. CD36 is a receptor/transporter which binds fatty acids of lipoproteins. The objective of the present study was to examine the pleiotropic effects of pyridoxamine, especially CD36 expression in KK-A(y)/Ta mice with type 2 diabetic nephropathy. METHODS: KK-A(y)/Ta mice were divided into 2 groups as follows: pyridoxamine treatment group and a tap water group as controls. The urinary ACR, fasting serum insulin, TG and lipoprotein subclasses were measured as biochemical parameters. The renal expressions of malondialdehyde (MDA) were evaluated by immunohistochemistry. CD36 mRNA expressions in kidney and adipose tissue were also evaluated using real-time PCR. RESULTS: Pyridoxamine decreased levels of urinary ACR, serum TG, especially VLDL and fasting serum insulin. MDA accumulation in the pyridoxamine treated group was significantly lower than those in the non-treatment group. The CD36 accumulation and mRNA expressions in kidney and adipose tissue in the treatment group were significantly higher than those in the non-treatment group. CONCLUSIONS: It appears that pyridoxamine ameliorated lipid peroxidation and insulin resistance in KK-A(y)/Ta mice. This pleiotropic effect of pyridoxamine was related to CD36 expression in the kidney and adipose tissue.

Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-A(y)/Ta mice.

Advanced glycation end products (AGEs) from the Maillard reaction contribute to the pathogenesis of diabetes-associated complications such as diabetic nephropathy. In therapeutic interventions for reducing AGEs, many compounds have been reported as AGE inhibitors. The objective of the present study was to examine the effect of pyridoxamine (K-163), an AGE inhibitor, in type 2 diabetic KK-A(y)/Ta mice. KK-A(y)/Ta mice were given pyridoxamine (200 or 400 mg/kg per day) starting at 8 weeks of age for 12 weeks. They were divided into 3 groups as follows: pyridoxamine 200 mg/kg per day treatment group (n = 10), pyridoxamine 400 mg/kg per day treatment group (n = 10), and a tap water group as the control group (n = 20). The urinary albumin/creatinine ratio (ACR), body weight (BW), levels of fasting and casual blood glucose, blood glycated hemoglobin (HbA(1c)), fasting serum insulin, triglyceride (TG), total cholesterol (T-Cho), and 3-deoxyglucosone (3DG), and systemic blood pressure were measured as biochemical parameters. N(epsilon)-(Carboxymethyl)lysine (CML) and nitrotyrosine accumulations in glomeruli were evaluated by immunohistochemical analyses. Transforming growth factor beta1 (TGF-beta1) and laminin-beta1 messenger RNA expressions in the kidneys were evaluated by real-time polymerase chain reaction. Pyridoxamine, especially at 400 mg/kg per day, improved the levels of urinary ACR, fasting serum TG, and 3DG. CML and nitrotyrosine accumulations in glomeruli were decreased. Furthermore, large doses of pyridoxamine prevented not only urinary ACR but also increases of BW, casual blood glucose, and HbA(1c). TGF-beta1 and laminin-beta1 messenger RNA expressions in kidneys were significantly lower than those in the controls. There were no significant changes in the levels of fasting blood glucose, serum T-Cho, and systemic blood pressure among all groups. It appears that pyridoxamine improved urinary ACR by its anti-AGE and anti-oxidant effects in the kidneys of KK-A(y)/Ta mice.