RELATIONSHIP BETWEEN P-GLYCOPROTEIN EXPRESSION AND CYCLOSPORINE-A IN KIDNEY - AN IMMUNOHISTOLOGICAL AND CELL-CULTURE STUDY

P-glycoprotein (P-gP), encoded in humans by the mdr-1 gene, acts physi ologically as an efflux pump to expel hydrophobic substances from cell s. This glycoprotein is closely related to multidrug resistance in tum or cells and can be modulated by cyclosporin A (CsA), We investigated the relationship between CsA and P-gp in 52 renal allograft biopsies a nd in cultures of Madin-Darby canine kidney (MDCK) renal tubule cells to determine whether the intrarenal accumulation of CsA or chronic sti mulation with the drug modified the expression of p-gp. Expression of P-gp and CsA was analyzed by immunohistochemistry. Immunostaining was evaluated semiquantitatively. Modulation of P-gP in MDCK cells after c hronic stimulation with CsA for 7, 30, and 60 days was analyzed by flo w cytometry. P-gp and CsA immunostaining in renal post-transplant biop sies showed considerable overlap in all cases (Spearman's test, r = 05 77, P < 0.001), After 7 days in vitro, the number of cells expressing P-gP increased progressively; a further increase in mean fluorescence was found after 60 days (P < 0.001, Student's t-test), Our findings su ggest that in non-neoplastic cells, CsA may stimulate P-gp as a mechan ism of detoxification. Individual differences in the adaptive response s to glycoprotein may be responsible for the appearance of nephrotoxic ity or a CsA-resistant rejection reaction in cases of overexpression o n lymphocytes and macrophages.