Experimental nephrotic syndrome induced by several immunologic and biochemical methods is associated with the development of tubulointerstitial nephritis (TIN). To investigate the hypothesis that severe sustained proteinuria plays a role in the pathogenesis of TIN, the renal interstitium in a model of protein-overload proteinuria was studied. After uninephrectomy, rats received daily injections of 1.0 g of bovine serum albumin (BSA) or saline (controls) until killing at 1, 2, 4, or 7 weeks. Sections of frozen renal cortex were stained with a panel of monoclonal antibodies reactive with subsets of rat lymphohemopoietic cells, and positive tubulointerstitial cells (TIC) were quantitated by epifluorescence microscopy. BSA rats developed proteinuria, with mean rat urinary albumin excretion rates at 1, 2, 3, and 6 weeks of 35.6+/-21.8, 97.2+/-46.1, 63.6+/-40.8, and 58.6+/-24.4 mg/24 hours, respectively (controls, 0.17+/-0.16 mg/24 hours). BSA was detectable in the plasma of experimental animals at all periods, with mean values of 26.8+/-3.8, 27.8+/-2.7, 20.3+/-6.2, and 7.0+/-1.1 mg/ml (controls, 0.03+/-0.04 mg/ml) at 1, 2, 4, and 7 weeks, respectively, whereas plasma anti-BSA antibodies were never detected. A significant mononuclear cell infiltrate was present in the interstitium of experimental animals at all periods. At 1 week, an influx of macrophages was evident that was identified by surface markers OX42 (75+/1000 TIC)(P less than 0.01) and Ia (58+/1000 TIC)(P less than 0.01). Macrophages dominated the infiltrate at all periods. By 2 weeks, a significant population of lymphocytes was also present that was identified by the surface marker OX19 (54+/1000 TIC)(P less than 0.01). This early lymphocytic infiltrate was a mixed lesion of T helper and T cytotoxic cells. However, at 4 and 7 weeks, most lymphocytes expressed the OX8 cytotoxic T cell marker. The proximal tubules of proteinuric rats expressed vimentin intermediate filaments, a marker of tubular epithelial cell regeneration after injury. In BSA rats, C3 and neoantigens of the membrane attack complex of complement without IgG were present along the luminal border of many tubular epithelial cells. The interstitial infiltrate was confirmed by light microscopy. By 4 weeks, focal areas of chronic interstitial disease were evident consisting of tubular atrophy and interstitial fibrosis. In a second study, one group of BSA-treated rats was depleted of circulating T lymphocytes by daily parenteral injections of monoclonal antibody OX19.(ABSTRACT TRUNCATED AT 400 WORDS)