Hydrocarbon-induced hyaline droplet nephropathy in male rats during senescence

Male rats administered unleaded gasoline rapidly develop nephropathy characterized by accumulation of hyaline droplets in cells of the proximal convoluted tubules (PCT). This acute response is implicated in development of renal carcinoma in male rats exposed chronically to wholly volatilized gasoline. A major constituent of hyaline droplets is α_2u-globulin, a protein of hepatic origin for which the rate of synthesis declines during aging. Little information, however, is presently available on possible age-dependent susceptibility of male rats to hydrocarbon-induced nephropathy. In kidneys of untreated male Fischer 344 rats the number of constitutive hyaline droplets declined progressively with increasing age. Electrophoresis of renal cortical homogenates revealed a protein with M_r about 18 × 10³, probably α_2u-globulin, in young (3.5 months old) male rats and total absence of this protein in aged (26 months old) males. RIA confirmed that constitutive levels of renal and hepatic α_2u-globulin in old rats were less than 1.5% of those in young adults. Unleaded gasoline (0.4 ml/kg/day, po, 5 days) caused accumulation of hyaline droplets in renal PCT of 3.5-month-old males accompanied by a marked increase (about twofold) in the renal content of α_2u-globulin, whereas the same treatment was without effect in 26-month-old rats. Finally, in the renal cortex of young rats the activities of the lysosomal proteases cathepsin B and D were increased following gasoline administration, presumably in response to protein accumulation. However, in 26-month-old rats cathepsin B activity was unaffected, while cathepsin D was increased by gasoline administration. Thus, we conclude that animal age is an important determinant in the development of hydrocarbon-induced nephropathy and only rats which produce large amounts of α_2u-globulin are susceptible to development of this pathology.