Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-alpha-dependent pathway.
This study investigated the role of advanced glycation end products (AGEs) in mediating protein kinase C (PKC) isoform expression in diabetic nephropathy. In vitro, vascular smooth muscle cells incubated in a high-glucose (25-mmol/l) medium demonstrated translocation and increased expression of PKC-alpha as compared with those from a low-glucose (5-mmol/l) environment. Coincubation with the cross-link breaker ALT-711 and, to a lesser extent, with aminoguanidine, an inhibitor of AGE formation, attenuated the increased expression and translocation of PKC-alpha. Streptozotocin-induced diabetic rats were randomized to no treatment, treatment with ALT-711, or treatment with aminoguanidine. Diabetes induced increases in PKC-alpha as well as in the -betaI, -betaII, and -epsilon isoforms. Treatment with ALT-711 and aminoguanidine, which both attenuate renal AGE accumulation, abrogated these increases in PKC expression. However, translocation of phosphorylated PKC-alpha from the cytoplasm to the membrane was reduced only by ALT-711. ALT-711 treatment attenuated expression of vascular endothelial growth factor and the extracellular matrix proteins, fibronectin and laminin, in association with reduced albuminuria. Aminoguanidine had no effect on VEGF expression, although some reduction of fibronectin and laminin was observed. These findings implicate AGEs as important stimuli for the activation of PKC, particularly PKC-alpha, in the diabetic kidney, which can be directly inhibited by ALT-711.
Thallas-Bonke
Vicki
V
Danielle Alberti Memorial Centre for Diabetes Complications, Vascular Division, Baker Medical Research Institute, P.O. Box 6492, St. Kilda Rd. Central, Melbourne, Australia. vicki.thallas@baker.edu.au.
Lindschau
Carsten
C
Rizkalla
Bishoy
B
Bach
Leon A
LA
Boner
Geoffrey
G
Meier
Matthias
M
Haller
Hermann
H
Cooper
Mark E
ME
Forbes
Josephine M
JM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D007672:Kidney Cortex / Q000187:drug effects / Q000473:pathology; D008297:Male; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051571:Protein Kinase C-alpha; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*
D001786:Blood Glucose; D016326:Extracellular Matrix Proteins; D017127:Glycation End Products, Advanced; D006146:Guanidines; D013844:Thiazoles; C406794:alagebrium; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; C004479:pimagedine