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 postglomerular 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 5 0 mg/kg. Age-matched control rats received buff e r 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 . 1 5 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 / 2 . 1 1 mg/24 h; control 0.74 / 1 . 5 7 mg/24 h, P < 0.

Attenuation of Extracellular Matrix Accumulation in Diabetic Nephropathy by the Advanced Glycation End Product Cross-Link Breaker ALT-711 via a Protein Kinase C-α−Dependent Pathway

“…Furthermore, a separate study in experimental diabetes has demonstrated no effect of aminoguanidine on PKC activity in the context of reduced AGEs (27), thereby confirming our current results. Other studies, however, have shown that treatment with aminoguanidine attenuates increases in PKC activity after 24 weeks of diabetes in glomeruli (8), retina, and mesenteric artery (28), although specific PKC isoforms were not addressed in that study. It appears likely that some of the differences seen in that study relate to the lack of examination of nonglomerular sources of PKC, such as tubules, which in this and previous studies have been shown to be major sites of expression and phosphorylation of various PKC isoforms (6,7).…”

“…Increases in PKC activity have been identified in vivo in renal glomeruli from streptozotocin-induced diabetic rats (8,9) and cells cultured under high-glucose conditions (10). Several studies have also reported attenuation of experimental diabetic nephropathy with the PKC-␤I inhibitor, LY333531 (11,12).…”

“…In addition, PKC may be directly activated by AGEs (17), possibly via a specific AGE-receptor subtype (18). Previous studies by our own group have identified abrogation of diabetes-associated increases in PKC activation with the AGE inhibitor, aminoguanidine (8).…”

Diabetic Nephropathy: Current and Novel Therapeutic Approaches to Prevent Its Development and Progression

“…Modulation of PKC activity within the diabetic kidney has also been exhibited by various vitamin B derivatives (Babaei-Jadidi, Karachalias et al Hammes, Du et al 2003). Interestingly, both ACEi and aminoguanidine prevent diabetes associated increases in PKC  activation in renal glomeruli (Osicka, Yu et al 2000). The effects of aminoguanidine and ACEi on PKC  activity were also observed at other sites of vascular injury including the retina and mesenteric vascular bed (Osicka, Kiriazis et al 2001;Miyata, van Ypersele de Strihou et al 2002).…”

The role of ramipril in the therapy of diabetic nephropathy

“…A diabetes és ennek kapcsán a magas vércukorszint indukálta proteinkináz-C aktivitásának fokozódása állatkísérletes adatok alapján központi szerepet tölt be a vascularis károsodások kialakulásában. Ugyanígy állatkísérletes adatok támaszt-ják alá, hogy ramiprillel csökkenteni lehet a diabetes kiváltotta proteinkináz-C-aktivitás fokozódását nemcsak a glomerulusokban, hanem a mesenterialis erekben és a retinában is [36,37]. Az Ang II által stimulált vascularis endothelialis növekedési faktor gátlása ramiprillel a retinavédő hatás egyik lehetséges magyarázata [38].…”