EXPRESSION AND FUNCTION OF P-GLYCOPROTEIN IN HUMAN MESANGIAL CELLS

P-glycoprotein (PGP), responsible for multidrug resistance (MDR) in ca ncer cells, is normally expressed in kidney proximal tubules and mesan gium. PGP expression and function were studied in human mesangial cell cultures. MDR1 gene expression was demonstrated by reverse transcript ion-polymerase chain reaction. PGP expression was determined using MRK 16 monoclonal antibody and its function was assessed by the efflux of rhodamine-123 (R123). R123 efflux had a halftime of 25 +/- 5 s. Efflux was inhibited by cyclosporin A (10 mu M), verapamil (10 mu M), and vi nblastine (100 mu M) with half times of 380, 535, and 312 s, respectiv ely. Incubation with MDR1-antisense oligonucleotide decreased R123 eff lux (half time = 304 s). Verapamil, cyclosporin A, and PSC-833 augment ed the cytotoxicity of Adriamycin by reducing the 50% maximal growth-i nhibitory dose from 730 nM to 130, 110, and 90 nM, respectively. We co nclude that human mesangial cells express MDR1 and demonstrate xenobio tic transport inhibitable by several known PGP substrates. Concomitant exposure of mesangial cells to PGP-transported drugs causes intracell ular accumulation of toxic PGP substrates and ultimately damages the m esangial cells.