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      Effect of a Novel Immunosuppressant, FK 506, on Autoimmune Glomerulonephritis in Brown Norway Rats

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          Mercuric-chloride (HgCl<sub>2</sub>) induces a lymphoproliferative disorder and autoimmune glomerulonephritis in Brown Norway rats. The effects of a new immunosuppressant FK 506 on this model of glomerulonephritis were studied. Brown Norway rats were treated with HgCl<sub>2</sub> according to a standard protocol (HgCl<sub>2</sub> 1 mg/kg s.c. 3 times/ week). Rats developed proteinuria at day 7, which reached a plateau level at day 14. On day 14, renal histology showed prominent mesangial cellular proliferation and the expansion of mesangial matrix. Electron microscopic study showed the effacement of visceral epithelial foot processes and the microvillous transformation of the visceral epithelium. Immunofluorescence study showed a strong linear staining for IgG and the adhesion molecule ICAM-1 in all glomeruli. Coadministration of FK 506 (1 mg/kg s.c. daily) prevented the appearance of proteinuria at day 14 (621.4 ± 30.5 vs. 2.2 ± 2.7 mg/day) and the morphological lesions. These findings suggest that FK 506 could be useful for the therapy of certain types of human glomerulonephritis.

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          A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase.

          The structurally novel macrolide FK506 (refs 1,2) has recently been demonstrated to have potent immunosuppressive activity at concentrations several hundredfold lower than cyclosporin A (CsA). Cyclosporin A, a cyclic peptide, has found widespread clinical use in the prevention of graft rejection following bone marrow and organ transplantation. The mechanisms of immunosuppression mediated by FK506 and CsA appear to be remarkably similar, suggesting that these unrelated structures act on a common receptor or on similar molecular targets, perhaps the CsA receptor, cyclophilin, which has recently been shown by Fischer et al. and Takahashi et al. to have cis-trans peptidyl-prolyl isomerase activity. We have prepared an FK506 affinity matrix and purified a binding protein for FK506 from bovine thymus and from human spleen. This FK506-binding protein (FKBP) has a relative molecular mass (Mr) of approximately 14,000(14K), a pI of 8.8-8.9, and does not cross-react with antisera against cyclophilin. The first 40 N-terminal residues of the bovine and 16 residues of the human FKBP were determined; the 16-residue fragments are identical to each other and unrelated to any known sequences. This protein catalyses the cis-trans isomerization of the proline amide in a tetrapeptide substrate and FK506 inhibits the action of this new isomerase. The FKBP and cyclophilin appear to be members of an emerging class of novel proteins that regulate T cell activation and other metabolic processes, perhaps by the recognition (and possibly the isomerization) of proline-containing epitopes in target proteins.
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            Susceptibility to Mercuric Chloride-Induced Glomerulonephritis is Age-Dependent: Study of the Role of IFN-γ


              Author and article information

              S. Karger AG
              10 February 1999
              : 81
              : 2
              : 215-220
              aFifth Department of Internal Medicine, Hyogo College of Medicine, Hyogo, bSchool of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka, and cFirst Department of Medicine, Osaka University, Osaka, Japan
              45279 Nephron 1999;81:215–220
              © 1999 S. Karger AG, Basel

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              Page count
              Figures: 4, Tables: 1, References: 25, Pages: 6
              Self URI (application/pdf): https://www.karger.com/Article/Pdf/45279
              Original Paper

              Cardiovascular Medicine, Nephrology

              FK 506, HgCl2 , Brown Norway rat


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