Female Nagase analbuminemic rats (NAR) are profoundly hypertriglyceridemic and develop proteinuria and glomerulosclerosis when aging and after uninephrectomy (UNX). Ovariectomy (OVX) markedly decreases plasma triglyceride levels in this species. This study evaluated whether decreasing triglyceride levels by OVX could prevent renal disease or alleviate its progression in UNX female NAR. Female NAR underwent OVX at 0, 12, 24, or 36 wk after UNX. In the absence of OVX, the animals developed progressive proteinuria from 18 wk after UNX and showed extensive glomerular sclerosis, lipid deposition, and hypertrophy at euthanasia (49 wk after UNX). These changes were prevented by OVX carried out at 0 or 12 wk, and attenuated by OVX at 24 wk after UNX. If performed at 36 wk after UNX, OVX had no effect on glomerulosclerosis, although it reduced proteinuria. In 95% (20 of 21) of the rats with proteinuria over 10 mg/day, proteinuria decreased in the first 6 wk after OVX. The percentage decrease in proteinuria correlated inversely with the glomerulosclerosis score at euthanasia (r = -0.58, P < 0.01). OVX had no effect on hyperfiltration and hyperperfusion in the UNX rats. OVX consistently reduced plasma triglyceride levels in rats both with and without proteinuria, and it also reduced plasma cholesterol, but only in conjunction with reduction in proteinuria. It was concluded that OVX in UNX female NAR prevents glomerulosclerosis if performed before proteinuria and attenuates further development of established renal disease if performed in a timely manner. This study's data suggest that in UNX female NAR, the lowering of plasma triglyceride levels plays a central role in the renoprotective action of OVX.