In both the nephrotic syndrome (NS) and hereditary analbuminemia in the Nagase analbuminemic rat (NAR), the plasma protein concentration is nearly normal since albumin is replaced by several high molecular weight proteins. In rats these include the protease inhibitors alpha 2-macroglobulin (alpha 2M), a 720 kDa positive acute phase protein (APP) and alpha 1-inhibitor 3 (alpha 1-I3), a 180 kDa negative APP. There is no known stimulus to increase alpha 1-I3 synthesis, but like albumin and other negative APPs its synthesis decreases during inflammation by transcriptional down-regulation. In hypoalbuminemic states gene transcription of other positive and negative APPs is increased. We report that alpha 2M was increased significantly (12-fold) in NAR and by approximately 50-fold in rats with NS compared to control. The alpha 1-I3 concentration was twice normal in NAR or NS compared to controls, providing approximately half of the total plasma protein. Infusion of human albumin into NAR to raise albumin levels > 20 mg/ml for 24 hours caused a significant decrease in alpha 1-I3 (24.8 +/- 0.6 to 18.7 +/- 0.6 mg/ml, P < 0.0001), equal in magnitude to that caused by 250 micrograms/100 g of endotoxin (23.0 +/- 1.1 to 18.6 +/- 0.6, P < 0.01). The effect of albumin was not an acute phase response since it also suppressed alpha 2M (239 +/- 10 to 205 +/- 11 micrograms/ml, P < 0.005). Turnover of 125I labeled alpha 2M and alpha 1-I3 was then measured in controls, NAR and in two models of the nephrotic syndrome in rats (Heymann nephritis, HN; adriamycin-induced, ADR), yielding fractional catabolic rates (FCR), which at steady state equals synthesis. The serum alpha 2M concentration was increased approximately equal to 50-fold and was proportional to synthesis (r = 0.91 P < 0.001). alpha 2-Macroglobulin synthesis increased by 12-fold in NAR and 50-fold in NS. In contrast, hepatic alpha 2M mRNA increased only 30% in NAR and twofold in NS, suggesting post-transcriptional regulation. Fractional catabolic rates were not decreased and played no role in increasing serum alpha 2M in NS or NAR. The alpha 1-I3 concentration and synthesis increased twofold from controls in both NAR and NS. However, hepatic alpha 1-I3 mRNA was not increased in NAR and increased only 50% in NS. Unlike alpha 2M, serum alpha 1-I3 correlated negatively with FCR (-r = 0.66, P < 0.01). In conclusion, both alpha 1-13 and alpha 2M concentration are increased in hypooncotic states by increased synthesis regulated post-transcriptionally, supporting plasma protein concentration when albumin is lost in urine or not synthesized.