Association between very-low-density lipoprotein and glomerular injury in obese Zucker rats

Obese Zucker rats spontaneously develop lipoprotein abnormalities, proteinuria, mesangial expansion and glomerulosclerosis. Previous studies have implicated these lipoprotein abnormalities in the pathogenesis of the progressive renal injury which these rats develop. The present study was designed to examine the chronological development of very-low-density lipoprotein (VLDL) abnormalities and renal injury. Obese and lean Zucker rats were maintained on a standard rat diet and sacrificed at 6, 11, 17, 23, 28, and 34 weeks of age. Renal tissue was examined histologically, serum was assayed for lipoproteins, and 24-hour urinary protein excretion determined. Hypertriglyceridemia, elevated VLDL-cholesterol and VLDL-triglycerides were seen at as early as 6 weeks of age in obese rats at a time when other lipoprotein fractions were normal. By 23 weeks, proteinuria developed in obese animals and renal tissue showed increased mesangial matrix, hypercellularity and glomerulosclerosis with lipid deposition noted in the mesangium. All of these abnormalities worsened during the 34 weeks of study at a time when almost all of the total circulating cholesterol was carried by VLDL rather than low-density lipoprotein (LDL), the predominant carrier of circulating cholesterol. These data suggest that increased lipoproteins with atherogenic potential, specifically cholesterol-rich VLDL and triglyceride-rich VLDL particles, correlated positively with the development of renal injury and glomerulosclerosis in obese Zucker rats. They further support a hypothesis that the increased appearance of atherogenic lipoproteins, particularly cholesterol-rich VLDL, may be associated with proteinuria and progressive glomerular injury.