Urinary Excretion of α₂_u-Globulin and Albumin by Adult Male Rats following Treatment with Nephrotoxic Agents

Abstract

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 α_2u-globulin. On the other hand, MAL which inhibits the reabsorption of proteins, increased the loss of both α_2u 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 α_2u and albumin. Renal loads and excretion of α_2u and albumin were measured in male rats maintained on 0, 20, and 50% casein diets. On the protein-free diet, the excretion of both α_2u and albumin was reduced (less than 1 mg daily); their renal loads were almost totally reabsorbed. On a 50% casein diet the reabsorption of α_2u was reduced from a normal of 60% to 10% of the renal load. Thus, the high protein diet increased the excretion of α_2u 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 α_2u and albumin. High protein diets appear to reduce selectively the reabsorption of α_2u -globulin, thereby increasing its excretion in the urine.

Implications for risk assessment of suggested nongenotoxic mechanisms of chemical carcinogenesis.

“…Hydrocarbons or their metabolites that bind reversibly to x21 do not increase the level of hepatic synthesis of this protein (40). a2-Microglobulin is secreted into the blood, filtered through the glomerulus, and partially reabsorbed (50%) by endocytosis into proximal tubule epithelial cells of the P2 segment (41). The unabsorbed fraction is excreted in the urine while the reabsorbed portion is presumably hydrolyzed to amino acids after fusion of endocytotic vesicles with epithelial cell lysosomes.…”

Hazard evaluation of chemicals that cause accumulation of alpha 2u-globulin, hyaline droplet nephropathy, and tubule neoplasia in the kidneys of male rats.

“…In the mature male rat, approximately 50 mg of a2U-g is filtered per day; 40% of the filtered protein is excreted in the urine and 60% undergoes reabsorption and catabolism (81,82). It is catabolized slowly relative to most other proteins in the glomerular filtrate, with a half-life in plasma, kidney cytosol, or lysosomal preparations of5-8 hr (32,34,83).…”

“…a2.-Globulin levels are reduced by more than 90% by 22 months of age in male rats and are virtually undetectable in senescent animals (71,78,79). Renal cortical tissue content (41) and urinary excretion (78,80) of a2.-g reflect the same agerelated trends as synthesis in the liver.In the mature male rat, approximately 50 mg of a2U-g is filtered per day; 40% of the filtered protein is excreted in the urine and 60% undergoes reabsorption and catabolism (81,82). It is catabolized slowly relative to most other proteins in the glomerular filtrate, with a half-life in plasma, kidney cytosol, or lysosomal preparations of5-8 hr (32,34,83).…”

Hyaline Droplet Accumulation in Rodent Kidney Proximal Tubules: An Association with Histiocytic Sarcoma

“…-@is ofdiverse chemical substances can invoke a marked increase in eosinophilic protein droplets within the second (P2) segment of the proximal convoluted tubule of male rats as the first step in a nephropathic sequence. The list of substances includes unleaded gasoline (38), tetrachloroethylene (a solvent widely used in the laundry and dry cleaning industry) (1 6), (35) and its subsequent filtration via the kidney, where a substantial proportion of the low-molecular-weight protein is reabsorbed and catabolized in the proximal tubule (28). Such is not the case in female rats, mice of either sex, or humans.…”