ALT-946 and Aminoguanidine, Inhibitors of Advanced Glycation, Improve Severe Nephropathy in the Diabetic Transgenic (mREN-2)27 Rat

ALT-946 and Aminoguanidine, Inhibitors of Advanced Glycation, Improve Severe Nephropathy in the Diabetic Transgenic (mREN-2)27 Rat Jennifer L. Wilkinson-Berka 1 , Darren J. Kelly 2 , Suzanne M. Koerner 1 , Kassie Jaworski 1 , Belinda Davis 3 , Vicki Thallas 3 and Mark E. Cooper 3 1 Department of Physiology, University of Melbourne, Parkville, Victoria, Australia 2 Department of Medicine, St. Vincent’s Hospital, Fitzroy, Victoria, Australia 3 Department of Medicine, the Austin Repatriation Hospital Medical Centre, West Heidelberg, Victoria, Australia Abstract 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. Footnotes Address correspondence and reprint requests to Dr. Jennifer L. Wilkinson-Berka, Department of Physiology, The University of Melbourne, Grattan Street, Victoria, Australia, 3010. E-mail: j.berka{at}physiology.unimelb.edu.au . Received for publication 21 May 2002 and accepted in revised form 22 July 2002. M.C. has received funds from Alteon Corporation to conduct studies on new drugs to treat diabetes complications. AER, albumin excretion rate; AG, aminoguanidine; AGE, advanced glycation end product; GFR, glomerular filtration rat