RESISTANCE TO GLOMERULAR INJURY IN THE DIABETIC BIOBREEDING RAT

This study was designed to determine whether the diabetic BioBreeding rat develops significant renal injury following long-term moderate to severe hyperglycaemia. Diabetic and control rats were followed from th e onset of diabetes (2-4 months) to 18 months of age. Frank proteinuri a and/or albuminuria were always absent. Glomerular filtration rate, m easured by inulin clearance (ml min(-1) (100 g body weight)(-1)), was significantly higher in diabetic rats than in controls at 10, 12 and 1 8 months of age. Advanced glycosylation end product cross-links assess ed by percentage solubility of tail tendon collagen were moderately in creased in diabetic compared with control animals. Urinary excretion o f advanced glycosylation end-products in unfractionated urine and in u rine fractionated for low molecular mass peptides (< 10 kDa) was 11-fo ld greater in the diabetic rats than in the control group. Urinary exc retion of nitric oxide metabolites (nmol NO2- and NO3- (24 h)(-1)) wer e significantly (P < 0.05) greater in diabetic rats than in controls a fter 8 months of age. Mild histopathology resembling human diabetic ne phropathy, including increased mesangial volume and glomerular basemen t membrane thickness, was detected at 18 months of age. The findings o f hyperfiltration and mild glomerular morphological changes in diabeti c BioBreeding rats are similar to the abnormalities seen in stage 2 hu man diabetic nephropathy. We hypothesize that two factors which may co ntribute to the resistance or tolerance to renal injury in the BioBree ding diabetic rat are increased nitric oxide production and the decrea sed accumulation of advanced glycosylation end-products.