Prevention of albuminuria by aminoguanidine or ramipril in streptozotocin-induced diabetic rats is associated with the normalization of glomerular protein kinase C

This study examined whether the prevention of diabetes-related albuminuria by aminoguanidine (AG) or ramipril (RAM) may be mediated by a common postgl omerular basement membrane renal intracellular mechanism involving protein kinase C (PKC). The renal handling of albumin was examined over 24 weeks in control and streptozotocin (STZ)-induced diabetic rats. A radioimmunoassay (RIA) that measures intact albumin, and intravenously injected tritium-lab eled rat serum albumin, was used to assess the proportion of intact albumin and albumin fragments in urine. Diabetes was induced in male Spragne-Dawle y rats by the intravenous administration of STZ at a dose of 50 mg/kg. Age- matched control rats received buffer alone. Diabetes was characterized by a n increase in blood glucose (>15 mmol/l), an increase in GHb (means at 24 w eeks 29.3 +/- 1.1%; control 6.1 +/- 0.1%, P < 0.005), an increase in glomer ular filtration rate (GFR) (4.13 +/- 0.15 ml/min; control 3.54 +/- 0.19 ml/ min, P < 0.005), an increase in intact albumin excretion rate (expressed as geometric mean 11.64 x/divided by 2.11 mg/24 h; control 0.74 X/divided by 1.57 mg/24 h, P < 0.005) as measured by RIA, and an increase in glomerular PKC activity (26.83 +/- 2.38 pmol . mg(-1) . min(-1); control 14.6 +/- 2.99 pmol . mg(-1) . min(-1), P < 0.005). Treatment of diabetic rats with eithe r AG or RAM prevented the rise in intact albuminuria and glomerular PKC act ivity. Renal lysosomal cathepsin activity decreased in diabetic rats and th is was not prevented by AG or RAM. Neither drug affected glycemic control o r GFR, but RAM reduced systolic blood pressure (BP), whereas AG did not. Th ese data indicate that urinary excretion of intact albumin and albumin-deri ved fragments in diabetes may be modulated independently of glycemic contro l (AG and RAM) and systolic BP (RAM). While both drugs are known for their different mechanisms of action, the fact that both prevent diabetes-related increases in glomerular PKC activity and albuminuria supports the hypothes is that PKC plays a central role in the development of diabetic nephropathy .