Aldose reductase gene expression is increased in insulin-dependent diabetes mellitus (IDDM) with nephropathy. Epidemiology studies in patients with IDDM and noninsulin-dependent diabetes mellitus (NIDDM) are consistent with the hypothesis that a genetic factor(s) influences the risk for kidney disease of diabetes mellitus (KDDM). Aldose reductase (AR), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene product. The present study explored the hypothesis that AR gene expression is increased in peripheral blood mononuclear cells obtained from patients with KDDM. We studied four groups of volunteers: group I, normal subjects; group II, IDDM without nephropathy; group III, IDDM with kidney disease; and group IV, nondiabetics with kidney disease. AR messenger ribonucleic acid was measured by a ribonuclease protection assay. The results are expressed as the mean and 95% confidence interval (CI) of the AR/beta-actin messenger ribonucleic acid molar ratios (AR/beta-actin R). Among diabetics, the AR/beta-actin R was higher in group III (0.088; CI, 0.068-0.108) than in group I (0.045; CI, 0.033-0.057; P < 0.01). There were no significant differences in age, hemoglobin A1c, or duration of diabetes between groups II and III (P = NS). The AR/beta-actin R in group III was also higher than that in group II (0.045; CI, 0.030-0.060; P < 0.01) or group IV (0.019; CI, 0.011-0.027; P < 0.001). In contrast, among nondiabetics, AR/beta-actin R values were 2-fold lower in group IV than in group I (P < 0.01). The results of this study are consistent with the hypothesis that the degree of AR gene expression modulates the risk of KDDM.