8-oxo-7-8-dihydrodeoxyguanine and Diabetic-Nephropathies

Podocytes participate in the formation and regulation of the glomerular filtration barrier. Loss of podocytes occurs during the early stages of diabetic nephropathy and impairs glomerular filtration. Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as anti-diabetic agents in clinical practice. In this study, we showed that gemigliptin, a novel DPP-4 inhibitor, reduced podocyte apoptosis in type 2 diabetic db/db mice without reducing hyperglycemia. Gemigliptin (100mg/kg/day) was administered orally for 12 weeks in db/db mice. Blood glucose levels and albuminuria were measured. The renal cortex was collected for histological examination, and molecular assays were used to detect 8-hydroxydeoxyguanosine, advanced oxidation protein products (AOPP), the receptor for advanced glycation end products (RAGE), and integrin-linked kinase (ILK). Type 2 diabetic db/db mice exhibited albuminuria, renal histopathological changes, and podocyte loss. Administration of gemigliptin to db/db mice suppressed albuminuria, enzyme activity and expression of DPP-4, and podocyte apoptosis. The effect of gemigliptin on diabetes-induced podocyte loss was associated with the suppression of oxidative damage, AOPP accumulation, RAGE expression, and ILK expression. These results indicate the possible benefits of using gemigliptin in diabetes patients to treat renal impairment without affecting glycemic control.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Advanced Oxidation Protein Products; Albuminuria; Animals; Apoptosis; Blood Glucose; Cytoprotection; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glomerular Filtration Rate; Guanine; Male; Mice, Inbred C57BL; Piperidones; Podocytes; Protein Serine-Threonine Kinases; Pyrimidines; Receptor for Advanced Glycation End Products

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.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blood Glucose; Cholesterol; Cystatin C; Cystatins; Diabetic Nephropathies; Glycated Hemoglobin; Guanine; Hypoglycemic Agents; Insulin; Kidney; Malondialdehyde; Obesity; Oxidation-Reduction; Phospholipids; Pioglitazone; Rats; Rats, Zucker; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Thiazolidinediones; Transforming Growth Factor beta; Triglycerides