EARLY INFLUX OF GLOMERULAR MACROPHAGES PRECEDES GLOMERULOSCLEROSIS INTHE OBESE ZUCKER RAT MODEL

Because hyperlipidemia and macrophage influx appear to play a key role in the genesis of renal glomerulosclerosis, this study examined the t emporal relationship between hyperlipidemia (triglycerides and cholest erol), mononuclear cell influx, changes in glomerular structure, and e xpansion of the extracellular matrices in obese Zucker rats, which rap idly develop hyperlipidemia and spontaneous glomerulosclerosis, Lean a nd 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 creatin ine levels were measured, and the presence of inflammatory cells in th e glomerulus was assessed by immunohistochemistry on kidney sections, Plasma lipids and insulin and macrophage density were significantly gr eater in obese than in lean rats as early as 1 month. Computer-assiste d image analysis was used to evaluate the glomerular domain surface ar eas, The morphometric measurements showed that glomeruli of obese rats rapidly became hypertrophied after 3 months, as a result of a very la rge increase in the mesangial domain. The expression of genes for extr acellular matrix components and inhibitors of extracellular matrix pro teinases (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 metalloprote inase inhibitors, each of which might participate in this matrix expan sion. Thus, the development of hyperlipidemia plus macrophage influx a t a very early age may initiate a sequence of events leading to glomer ulosclerosis later on.