ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mREN-2)27 rat.
The severe diabetic nephropathy that develops in the hypertensive transgenic (mRen-2)27 rat with streptozotocin (STZ) diabetes has previously been considered angiotensin II-dependent. Because metabolic pathways are also activated in the diabetic kidney, the present study aimed to determine whether renoprotection could be afforded with inhibitors of advanced glycation end products (AGEs), ALT-946, and aminoguanidine (AG). At 6 weeks of age, nondiabetic control and STZ diabetic Ren-2 rats were randomized to receive vehicle, ALT-946 (1 g/l), or AG (1 g/l) and were studied for 12 weeks. Systolic blood pressure was unchanged with diabetes, ALT-946, or AG. Both kidney weight and glomerular filtration rate were increased with diabetes and unchanged with ALT-946 or AG. ALT-946 and AG equally ameliorated glomerulosclerosis and medullary pathology; however, ALT-946 did reduce cortical tubular degeneration to a greater extent than AG. Albumin excretion rate, which was elevated with diabetes, was reduced with ALT-946 but not AG. AGE immunolabeling was increased in glomeruli and reduced with ALT-946 and AG. These findings indicate that even in the context of renal injury presumed to be primarily blood pressure- and/or angiotensin II-dependent, approaches that interfere with metabolic pathways such as inhibitors of AGE formation can confer renal protection in experimental diabetes.
Wilkinson-Berka
Jennifer L
JL
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia. j.berka@physiology.unimelb.edu.au
Kelly
Darren J
DJ
Koerner
Suzanne M
SM
Jaworski
Kassie
K
Davis
Belinda
B
Thallas
Vicki
V
Cooper
Mark E
ME
D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005919:Glomerular Filtration Rate; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006146:Guanidines / Q000627:therapeutic use*; D006834:Hydrazines / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000187:drug effects / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011922:Rats, Mutant Strains
D000577:Amides; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D006834:Hydrazines; D019001:Nitric Oxide Synthase; C468887:ALT-946; C004479:pimagedine