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Nephrotoxic agents such as puromycin aminonucleoside (PAN) and sodium maleate (MAL) have been used to induce experimental glomerular proteinuria and tubular disease, respectively. Current studies show that PAN caused a massive loss of albumin in the urine while not affecting the excretion of the smaller, sex-dependent alpha 2 mu-globulin. On the other hand, MAL which inhibits the reabsorption of proteins, increased the loss of both alpha 2 mu and albumin. Both nephrotoxic agents increased the excretion of albumin when administered to female rats. MAL-induced proteinuria was used as a direct measure of the renal load for alpha 2 mu and albumin. Renal loads and excretion of alpha 2 mu and albumin were measured in male rats maintained on 0, 20, and 50% casein diets. On the protein-free diet, the excretion of both alpha 2 mu and albumin was reduced (less than 1 mg daily); their renal loads were almost totally reabsorbed. On a 50% casein diet the reabsorption of alpha 2 mu was reduced from a normal of 60% to 10% of the renal load. Thus the high protein diet increased the excretion of alpha 2 mu while having little effect on the excretion of albumin. We suggest that dietary protein exerts two levels of control on the excretion of protein in the urine of the adult male rat. Protein-deficient diets stimulate the general reabsorption of proteins thereby minimizing the excretion of alpha 2 mu and albumin. High protein diets appear to reduce selectively the reabsorption of alpha 2 mu-globulin, thereby increasing its excretion in the urine.

The excretion of total urinary proteins (TUP) of rats beginning at weaning and extending to 12 months of age was correlated with the output of the sex-dependent alpha2u-globulin and albumin. At puberty, 40 days of age, the excretion of TUP corresponded to the output of alpha2u-globulin. At this age, alpha2u represented 30% of the total while albumin less than 10%. From 100 to 200 days of age, TUP remained constant while the excretion of albumin steadily increased. After 150--180 days of age, the concentrations of alpha2u and albumin in TUP were approximately equal. Thereafter, the excretion of albumin and TUP increased markedly whereas alpha2u excretion remained constant. At 373 days of age, albumin represented over 50--60% of the TUP while alpha2u was only 6--7%. Female rats which excrete little or no alpha2u exhibited a much lower level of proteinuria than the male during the first year. We suggest the existence of two phases of proteinuria in the male rat, namely, an early physiologic or alpha2u-globulinuric phase and a later albuminuric phase during which increasing quantities of plasma proteins, especially albumin, are lost.