Evolving concepts in advanced glycation, diabetic nephropathy, and diabetic vascular disease.
Advanced glycation endproducts (AGEs) have been postulated to play a role in the development of both nephropathy and large vessel disease in diabetes. However, it is still not clear which AGE subtypes play a pathogenetic role and which of several AGE receptors mediate AGE effects on cells. This review summarises the renoprotective effect of inhibitors of AGE formation, including aminoguanidine, and of cross-link breakers, including ALT-711, on experimental diabetic nephropathy and on mesenteric vascular hypertrophy. It also demonstrates similar effects of aminoguanidine and ramipril (an angiotensin converting enzyme inhibitor) on fluorescent and immunoassayable AGE levels, renal protein kinase C activity, nitrotyrosine expression, lysosomal function, and protein handling in experimental diabetes. These findings indicate that inhibition of the renin angiotensin system blocks both upstream and downstream pathways leading to tissue injury. We postulate that the chemical pathways leading to advanced glycation endproduct formation and the renin angiotensin systems may interact through the generation of free radicals, induced both by glucose and angiotensin II. There is also evidence to suggest that AGE-dependent pathways may play a role in the development of tubulointerstitial fibrosis in the diabetic kidney. This effect is mediated through RAGE and is TGF-beta and CTGF-dependent.
Jerums
George
G
Endocrine Unit, Austin Health, University of Melbourne, Studley Road, 3084 Heidelberg, Australia. endo@austin.unimelb.edu.au
Panagiotopoulos
Sianna
S
Forbes
Josephine
J
Osicka
Tanya
T
Cooper
Mark
M
D000419:Albuminuria / Q000188:drug therapy; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005544:Forecasting; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D011493:Protein Kinase C / Q000187:drug effects; D017257:Ramipril / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D013844:Thiazoles; C406794:alagebrium; D011493:Protein Kinase C; D017257:Ramipril; C004479:pimagedine