title: Prevention of albuminuria by aminoguanidine or ramipril in streptozotocin-induced diabetic rats is associated with the normalization of glomerular protein kinase C.
abstract: This study examined whether the prevention of diabetes-related albuminuria by aminoguanidine (AG) or ramipril (RAM) may be mediated by a common post-glomerular 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-labeled rat serum albumin, was used to assess the proportion of intact albumin and albumin fragments in urine. Diabetes was induced in male Sprague-Dawley 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 an increase in blood glucose (>15 mmol/l), an increase in GHb (means at 24 weeks 29.3+/-1.1%; control 6.1+/-0.1%, P<0.005), an increase in glomerular 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 times/divided by 2.11 mg/24 h; control 0.74 times/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 x mg(-1) x min(-1); control 14.6+/-2.99 pmol x mg(-1) x min(-1), P<0.005). Treatment of diabetic rats with either AG or RAM prevented the rise in intact albuminuria and glomerular PKC activity. Renal lysosomal cathepsin activity decreased in diabetic rats and this was not prevented by AG or RAM. Neither drug affected glycemic control or GFR, but RAM reduced systolic blood pressure (BP), whereas AG did not. These data indicate that urinary excretion of intact albumin and albumin-derived fragments in diabetes may be modulated independently of glycemic control (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 hypothesis that PKC plays a central role in the development of diabetic nephropathy.
authors.affiliation: Department of Medicine, University of Melbourne, Austin and Repatriation Medical Center, Heidelberg, Victoria, Australia.
authors.forename: T M
authors.initials: TM
authors.lastname: Osicka
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.forename: S
authors.initials: S
authors.lastname: Panagiotopoulos
authors.forename: S P
authors.initials: SP
authors.lastname: Clavant
authors.forename: Z
authors.initials: Z
authors.lastname: Kiriazis
authors.forename: R N
authors.initials: RN
authors.lastname: Pike
authors.forename: L M
authors.initials: LM
authors.lastname: Pratt
authors.forename: L M
authors.initials: LM
authors.lastname: Russo
authors.forename: B E
authors.initials: BE
authors.lastname: Kemp
authors.forename: W D
authors.initials: WD
authors.lastname: Comper
authors.forename: G
authors.initials: G
authors.lastname: Jerums
mesh_terms: D000419:Albuminuria / Q000517:prevention & control*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002403:Cathepsins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D007678:Kidney Glomerulus / Q000201:enzymology*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism*; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D011493:Protein Kinase C; D002403:Cathepsins; D017257:Ramipril; C004479:pimagedine