alt-946 and pimagedine

Diabetic nephropathy is the leading cause of end-stage renal disease, and both the incidence and prevalence of diabetic nephropathy continue to increase. Currently, various treatment regimens and combinations of therapies provide only partial renoprotection. It is obvious that new approaches are desperately needed to retard the progression of diabetic nephropathy. Recently, a number of new agents have been described that have the potential to delay the progression of diabetic kidney disease and minimize the growing burden of end-stage renal disease. These include inhibitors and breakers of advanced glycation end products, receptor antagonists for advanced glycation end products, protein kinase C inhibitors, NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase inhibitors, glycosaminoglycans, endothelin receptor antagonists, antifibrotic agents, and growth factor inhibitors. This review addresses these promising new therapeutic agents for delaying the progression of diabetic kidney disease.

Topics: Amides; Animals; Clinical Trials as Topic; Connective Tissue Growth Factor; Diabetic Nephropathies; Disease Progression; Endothelin Receptor Antagonists; Glycation End Products, Advanced; Glycosaminoglycans; Guanidines; Humans; Hydrazines; Kidney; NADPH Oxidases; Nitric Oxide Synthase; Pentoxifylline; Phosphodiesterase Inhibitors; Pyridines; Pyridoxamine; Pyrimidines; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vitamin B Complex

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Diabetes Mellitus; Diabetic Nephropathies; Glycation End Products, Advanced; Guanidines; Humans; Hydralazine; Hydrazines; Imidazoles; Olmesartan Medoxomil; Oxidative Stress; Pyridoxamine; Tetrazoles

Topics: Amides; Animals; Arteriosclerosis; Cardiovascular Diseases; Cataract; Clinical Trials as Topic; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Retinopathy; Disease Models, Animal; Drug Design; Glycation End Products, Advanced; Guanidines; Humans; Hydrazines; Hypoglycemic Agents; Thiadiazoles; Thiazoles; Thiazolidines

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.

Topics: Amides; Animals; Animals, Genetically Modified; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Inhibitors; Glomerular Filtration Rate; Glycation End Products, Advanced; Guanidines; Hydrazines; Immunohistochemistry; Kidney Cortex; Nitric Oxide Synthase; Organ Size; Rats; Rats, Mutant Strains