In order to elucidate the causal relationship between (Na(+)-K+)ATPase and diabetic nephropathy, we studied the erythrocyte (Na(+)-K+)ATPase activity in Type 2 diabetic patients, 20 with microalbuminuria and 27 without microalbuminuria and in 16 control subjects. (Na(+)-K+)ATPase activities in microalbuminuric patients (0.273 +/- 0.012 mumol Pi/mg protein/h, mean +/- SE) were significantly reduced compared with those without microalbuminuric patients (0.308 +/- 0.011 mumol Pi/mg protein/h, p < 0.05) and control subjects (0.330 +/- 0.011 mumol Pi/mg protein/h, p < 0.01). Microalbuminuric patients had higher systolic blood pressure (133 +/- 3 vs 124 +/- 3 mmHg, p < 0.05) and greater frequency of parental hypertension (50% vs 19%, p < 0.05) than those without microalbuminuria. (Na(+)-K+)ATPase activities in diabetic patients with hypertension were significantly reduced compared with those in diabetic patients without hypertension. Moreover, (Na(+)-K+)ATPase activities in diabetic patients with parental hypertension were significantly reduced compared with those in patients without parental hypertension. There was no difference in erythrocyte Na+ content between with and without microalbuminuria or hypertension or parental hypertension in diabetic patients. Erythrocyte Na+ content was significantly negatively correlated with (Na(+)-K+)ATPase activity in control subjects (r = -0.619, p < 0.05), but not in diabetic patients (r = -0.194). Plasma digitalis-like substances showed no correlation with (Na(+)-K+)ATPase activities in diabetic patients with microalbuminuria or hypertension or parental hypertension. We concluded that the reduction of erythrocyte (Na(+)-K+)ATPase activity may be related to a familial predisposition to arterial hypertension and may partly be responsible for the development of diabetic nephropathy in Type 2 diabetic patients.