Because hyperlipidemia and macrophage influx appear to play a key role in the genesis of renal glomerulosclerosis, this study examined the temporal relationship between hyperlipidemia (triglycerides and cholesterol), mononuclear cell influx, changes in glomerular structure, and expansion of the extracellular matrices in obese Zucker rats, which rapidly develop hyperlipidemia and spontaneous glomerulosclerosis. Lean and obese Zucker rats were fed a standard diet, and were euthanized at 14 days, 1, 3, 6, 9, and 12 months. Plasma lipid, insulin, and creatinine levels were measured, and the presence of inflammatory cells in the glomerulus was assessed by immunohistochemistry on kidney sections. Plasma lipids and insulin and macrophage density were significantly greater in obese than in lean rats as early as 1 month. Computer-assisted image analysis was used to evaluate the glomerular domain surface areas. The morphometric measurements showed that glomeruli of obese rats rapidly became hypertrophied after 3 months, as a result of a very large increase in the mesangial domain. The expression of genes for extracellular matrix components and inhibitors of extracellular matrix proteinases (TIMP-1 and TIMP-2) was monitored in microdissected glomeruli. Reverse transcription-polymerase chain reaction showed increases in mRNA for Type IV collagen and fibronectin and for the two metalloproteinase inhibitors, each of which might participate in this matrix expansion. Thus, the development of hyperlipidemia plus macrophage influx at a very early age may initiate a sequence of events leading to glomerulosclerosis later on.