Polymorphism of genes involved in anti-tubular basement membrane disease in rats

Abstract

Inbred strains of rats differ widely in their susceptibility to interstitial nephritis induced by rabbit renal tubular basement membrane (TBM) preparations. We now report that susceptibility is determined in part by an RT1-linked gene for effector cell responsiveness producing interstitial lesions. Furthermore, we also obtained evidence that the gene determining expression of the target TBM antigen is linked to the gene for albinism on the first linkage group. When non-susceptible rats lacking the TBM antigen but having the gene for cellular responsiveness were mated with non-susceptible rats which had the TBM antigen but lacked the gene for cellular responsiveness, the F1 hybrids were susceptible to the induction of interstitial nephritis. Although strains varied widely in the amount of anti-TBM antibody (alpha TBM-Ab) they produced, this variation does not appear to be controlled by RT1-linked genes, nor does the isotype or amount of antibody appear to be related to the susceptibility to infiltrating cellular lesions.

Inhibitory role of dietary protein restriction on the development and expression of immune-mediated antitubular basement membrane-induced tubulointerstitial nephritis in rats.

“…Highly enriched basement membrane fragments were sonicated, lyophilized, and stored in -700C. Soluble renal tubular antigens (SRTA) were made from these lyophilized membranes using collagenase digestion (14, 16,18 19). Direct immunoflourescence oftubular staining by aTBMAb was qualitatively graded from 0 to 4+ and expressed as mean±SEM for each group ( 16).…”

“…Soluble renal tubular antigens (SRTA) were made from these lyophilized membranes using collagenase digestion (14, 16,18 19). Direct immunoflourescence oftubular staining by aTBMAb was qualitatively graded from 0 to 4+ and expressed as mean±SEM for each group ( 16). Kidneys fixed in 10% formalin were sectioned and stained with hematoxylin and eosin, coded, and graded according to the extent of involved cortical area using established criteria (14, 19): 0 = normal; 0.5 = small focal areas of cellular infiltration; 1 = cellular infiltration and tubular damage involving <10% of the cortex; 2 = involvement up to 25% of the cortex; 3 = involvement up to 50-75% of the cortex, and 4 = extensive damage involving >75% of the cortex.…”

“…Scores for each experimental group were averaged and expressed as a mean±SEM. The presence of aTBM-Ab and titers of these antibodies were also determined by a solid-phase radioimmunoassay (16). 50 Ml of SRTA (12 MAg/ml) was added to the wells of PVC microtiter plates and kept at 4°C over night.…”

“…Primary interstitial nephritis has been implicated as a cause of 11-13% of acute renal failure, and in 25% of all cases of chronic renal failure (11,12). Because of its obvious importance, the mechanism and pathogenesis of tubulointerstitial nephritis has been intensively studied in experimental animals (13)(14)(15)(16)(17). Our laboratory has used a rat model of immune-mediated interstitial injury (anti-tubular basement membrane disease) which results in the development of antitubular basement membrane antibodies (aTBM-Ab),' mononuclear cell infiltrates, tubular atrophy, and fibrosis.…”

“…Our laboratory has used a rat model of immune-mediated interstitial injury (anti-tubular basement membrane disease) which results in the development of antitubular basement membrane antibodies (aTBM-Ab),' mononuclear cell infiltrates, tubular atrophy, and fibrosis. Nephritis is induced by immunizing Brown Norway rats (BN) with renal tubular basement membranes (RTA) in complete Freund's adjuvant (CFA) (16,17). aTBM-Ab appear within 10 d of immunization, and an intense infiltrate with associated fibrosis is seen by 3-4 wk.…”