Involvement of hyperglycemia in deposition of aggregated protein in glomeruli of diabetic mice.

The aim of this study was to clarify the influence of hyperglycemia on the deposition of aggregated protein in the glomeruli of diabetic mice. KK-A(y) mice injected with aggregated bovine serum albumin accumulated more of it in the glomeruli than did ICR mice. There were no histological alterations in the glomeruli of KK-A(y) mice. KK-A(y) mice given voglibose in mouse-chow for 2 weeks had significantly reduced blood glucose, glycated albumin, and hemoglobin A(1C) levels compared with control mice. The voglibose-treated KK-A(y) mice were injected with aggregated bovine serum albumin and accumulated significantly less albumin in the glomeruli than did the control mice. Pioglitazone decreased blood glucose levels compared with the control, and reduced the glomerular deposition of aggregated albumin. Glomerular aggregated bovine serum albumin levels and blood glucose levels were reduced significantly by the injection of insulin. Six times more advanced glycation endproducts were produced from aggregated bovine albumin than from non-aggregated bovine albumin on incubation with glucose and L-lysine in vitro. Glucose-loaded ICR mice generated more advanced glycation endproducts from aggregated albumin, and had more aggregated bovine albumin in the glomeruli. It was suggested that hyperglycemia contributes to an increase in the deposition of aggregated protein in glomeruli even early on in diabetes.

Pioglitazone improves obesity type diabetic nephropathy: relation to the mitigation of renal oxidative reaction.

Medications to treat hyperglycemia and hyperinsulinemia are expected to inhibit the accumulation of advanced glycation end-products in the diabetic kidney and improve renal function by inhibiting oxidative reactions. In this study, we examined the effect of pioglitazone, an insulin sensitizer, on diabetic nephropathy. Feed containing pioglitazone at 0.01 or 0.02% was given to Zucker-fatty rats for 27 weeks. Pioglitazone reduced plasma glucose, plasma insulin, and blood HbAlc levels. It also decreased plasma total cholesterol, triglyceride, phospholipid and cystatin C levels and inhibited the increase in urine of 8-hydroxydeoxyguanosine and in plasma of malondialdehyde. In the histopathological examinations, pioglitazone inhibited diffusive or nodular thickening of the mesangial matrix, atrophy of the proximal convoluted tubule, thickening of the basement membrane of the tubule, and mild cellular infiltration (mostly small lymphocytes) in the stroma. Furthermore, pioglitazone inhibited the mRNA expression of the receptor for advanced glycation end-products (RAGE) and that of transforming growth factor-beta. Long-term administration of pioglitazone improved hyperglycemia lipid profiles, hypercholesterolemia, and hyperinsulinemia and had a protective effect on diabetic nephropathy in Zucker-fatty rats.

Increase in the deposition of aggregated protein in the glomeruli of spontaneously diabetic mice.

The aim of this study was to investigate the disposal of aggregated protein in the glomeruli of spontaneously diabetic mice. Diabetic mice, KK-A(y) and db/db, and age-matched ICR mice were injected intravenously with aggregated bovine serum albumin (a-BSA) at 0.6 mg/g, and the glomeruli and the blood were obtained. Diabetic mice had larger amounts of a-BSA in their glomeruli than the ICR mice, threefold in KK-A(y) and twofold in db/db, at 3 h after the a-BSA injection. Additionally, the disappearance of a-BSA was retarded in the diabetic glomeruli. KK-A(y) displayed a-BSA in the glomeruli 24 h after the a-BSA injection and db/db did after 12 h, while the ICR did by 8 h. In spite of increases of insulin to similar degrees in both strains of diabetic mice after the a-BSA injection, blood glucose levels markedly decreased in KK-A(y) compared with db/db. There were no histopathological alterations in the glomeruli of the diabetic mice. Depositions of a-BSA were confirmed to be higher in the diabetic glomeruli by the immunofluorescence technique, and KK-A(y) displayed higher depositions of a-BSA than did db/db. The present study suggests that hyperglycemia is involved in the increased deposition of aggregated protein in the glomeruli and that the degradation of aggregated protein is retarded in diabetic glomeruli.