To elucidate the pathogenetic role of hyperlipidemia per se in the development of glomerulosclerosis, severely hyperlipidemic female analbuminemic rats (NAR) and mildly hyperlipidemic male NAR were studied for a period of 37 weeks after uninephrectomy (UNX). Plasma cholesterol increased from 6.3 +/- 0.4 (week 4) to 11.9 +/- 0.6 mmol/liter (week 37) in the female NAR, and from 4.3 +/- 0.1 to 6.4 +/- 0.5 mmol/liter in the male NAR in the same period. Plasma protein concentration was also consistently higher in female NAR (60 +/- 1 g/liter) as compared to male NAR (52 +/- 1 g/liter). Plasma viscosity was higher in female NAR than in male NAR, but there were no differences in blood viscosity. Proteinuria increased progressively in the UNX female NAR from 25 weeks after surgery, reaching a final value of 141 +/- 37 mg/day. No proteinuria occurred in the UNX male NAR (final value 15 +/- 2 mg/day). Glomerular capillary pressure, measured prior to the onset of proteinuria, was not significantly different in UNX female NAR and UNX male NAR. At the end of the study glomerulosclerosis and lipid deposition was only found in the UNX female NAR. Throughout the study hyperfiltration and hyperperfusion, relative to the one-kidney clearances of the sham-operated (2K) animals, were not different in UNX male and female NAR. No differences were observed in blood pressure. Hypertrophy, evaluated by glomerular diameters, was less pronounced in UNX female NAR (174 +/- 3 microns) than in UNX male NAR (190 +/- 7 microns). Glomerular diameters in 2K female and male NAR were similar (respectively 158 +/- 2 and 157 +/- 4 microns). Plasma apo B levels were similar (2K female NAR: 204 +/- 8 U; 2K male NAR 204 +/- 13 U), but cholesterol and triglyceride content of apo B-containing lipoproteins, namely VLDL, IDL and LDL, was increased twofold in the female NAR as compared to the male NAR, implying a larger particle size in the female NAR. Deposition of apo B and apo E was observed in the glomerular mesangium of UNX female NAR, particularly in sclerotic lesions. Glomerular apo A-I deposits were localized primarily in visceral epithelial cells and were not associated with sclerotic lesions. The development of proteinuria and glomerulosclerosis after UNX in female NAR but not in male NAR may depend upon differences in plasma lipoprotein composition, but is apparently not related to differences in whole kidney hyperfiltration and hyperperfusion, glomerular capillary pressure, or blood viscosity.