RENAL SECRETION OF XENOBIOTICS MEDIATED BY P-GLYCOPROTEIN - IMPORTANCE TO RENAL-FUNCTION IN HEALTH AND EXPLOITATION FOR TARGETED DRUG-DELIVERY TO EPITHELIAL CYSTS IN POLYCYSTIC KIDNEY-DISEASE

The proximal renal tubule is the major site of P-glycoprotein expressi on within the kidney; there is good evidence that P-glycoprotein expre ssion is not restricted to the proximal tubule occurring in thick asce nding limb and more distal segments. P-glycoprotein is expressed at th e apical brush-border membrane where it participates in ATP-dependent extrusion of substrates to urine. The Madin-Darby canine kidney (MDCK) dog-renal epithelial cell-line is a model for renal tubular P-glycopr otein mediated secretion. The apical membrane is rendered effectively impermeable to archetype substrates such as vinblastine by a combinati on of low intrinsic permeability and the operation of ATP-dependent ex port from cytosol to the apical (lumen) solution. Since the MDCK cell- line possesses features characteristic of the distal/collecting duct, this suggests a possible role for tubular expression at distal sites i n limiting back-diffusion and trapping of moderately lipophilic P-glyc oprotein substrates within the renal medulla after secretion in the pr oximal tubule and subsequent concentration resulting from tubular flui d reabsorption. The relative role of P-glycoprotein in mediating renal clearance of archetype P-glycoprotein substrates is discussed. Due to the absence of inhibitory agents of absolute specificity a definite a ssessment is not yet possible. The pharmacological importance of P-gly coprotein mediated transport in renal cells is discussed in relation t o renal transplantation and to treatment of renal carcinomas. The util ity of transgenic ''knockout'' animal models for assessing P-glycoprot ein function in renal clearance studies is highlighted. Renal polycyst ic disease is a major cause of renal insufficiency. Cysts arise from t ubules, but are closed structures with the epithelium oriented so that the brush-border is adjacent to the closed lumen. Bodipy-verapamil ha s been tested as a fluorescent substrate for P-glycoprotein mediated t ransepithelial secretion in MDCK-C5A epithelia (selected for their abi lity to form cysts in vitro) reconstituted first as a monolayer on per meable substrates. Net transepithelial secretion (J(net)) of [H-3]-vin blastine from basal to apical surfaces is inhibited by taxotere, verap amil and bodipy-verapamil. Bodipy-verapamil is itself subject to a sat urable transepithelial net secretion by MDCK-C5A epithelia. In MDCK-CS A cysts grown in hydrated collagen gel laser scanning confocal microsc opy shows that bodipy-verapamil is accumulated within the cyst lumen a bove medium concentrations. Renal cystic epithelial P-glycoprotein exp ression is exploitable to target cytotoxic P-glycoprotein substrates t o renal cysts. The possible advantages of targeting cytotoxic substrat es to renal cysts is discussed.