Renal mass reduction may lead to glomerular hypertrophy, proteinuria and focal glomerulosclerosis (FGS) in humans and rats. In humans and rats, females are less susceptible than males to these phenomena. This study was undertaken to evaluate the effect of male rat castration on the pathogenesis of proteinuria and FGS. Urinary protein was measured in 60-day-old male and female rats. Uninephrectomy was performed in all rats, and castration in half of the males. After 180 days, proteinuria, glomerular filtration rate (GFR) and blood biochemistry were determined. Kidneys were resected, weighed and subjected to morphologic studies. Following uninephrectomy, male rats developed severe proteinuria: 132.3 +/- 40.9 mg 24 h-1, most of which was accounted for by an albuminuria of 70.9 +/- 19.3 mg 24 h-1. In contrast, protein excretion in female and castrated male rats remained within normal limits: 8.0 +/- 1.8 and 4.2 +/- 0.5 mg 24 h-1, respectively. Mean glomerular volume in male rats was 1.18 +/- 0.08 x 10(6) microns3; much higher than in female rats, 0.84 +/- 0.04 x 10(6) micron3, and castrated male rats, 0.87 +/- 0.03 x 10(6) micron3 (P less than 0.005). On light and electron microscopy, glomeruli of female and castrated male rats were completely normal. In contrast, in four of seven male rats, mild glomerular changes were observed. They consisted mainly of mesangial expansion, electron-dense deposits and collapse of capillary loops. These data suggest that castration confers protection against the development of glomerular hypertrophy and proteinuria in uninephrectomized male rats. Endogenous testosterone may be associated with this development.