Sex differences in the incidence and progression of renal diseases suggest a protective role for estrogen. This study examined the role of estrogen receptor alpha (ERalpha)-mediated events in normal and diabetic renal and glomerular growth. Wild-type and ERalpha-null mice (ERKO) were observed over 2 wk of streptozocin-induced diabetes. Blood glucose was monitored, and insulin was given daily to maintain levels of 250-350 mg/dl. Body weight, kidney weight, glucose, insulin, renal transforming growth factor-beta(1), and glomerular area were examined for effects of sex, genotype, and diabetes. Genotype had no effect on glomerular or renal size in male mice regardless of metabolic state. Nondiabetic female ERKO mice had kidney weights approaching those of wild-type males and much greater than those of wild-type females (0.15 +/- 0.04 vs. 0.11 +/- 0.04 g; P < 0.001). When only diabetic mice were studied, sex and/or genotype showed no effect on renal weight. Diabetic female ERKO mice had smaller glomerular areas than wild types (2,799 +/- 159 vs. 3,409 +/- 187 microm(2); P = 0.01). Glomerular areas were similar in diabetic wild-type and ERKO males (3,020 +/- 199 vs. 3,406 +/- 176 microm(2)). Transforming growth factor-beta(1) levels, expressed as picograms per milligram total protein, were similar in diabetic wild-type and ERKO males (1.0 +/- 0.6 vs. 0.9 +/- 0.6). In diabetic females, wild types had significantly higher levels of this growth factor than ERKO mice (3.8 +/- 0.7 vs. 1.1 +/- 0.6; P = 0.005). ERalpha-mediated processes influence normal and diabetic renal and glomerular size, but only in female mice. These data do not support a protective role for ERalpha-mediated events in diabetic nephropathy.