Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma

Human kidney proximal tubule epithelia express the ATP-dependent export pum p for anionic conjugates encoded by the MRP2 (cMRP/cMOAT) gene (symbol ABCC 2). MRP2, the apical isoform of the multidrug resistance protein, is an int egral membrane glycoprotein with a molecular mass of approximately 190 kD t hat was originally cloned from liver and localized to the canalicular (apic al) membrane domain of hepatocytes. In this study, MRP2 was detected in hum an kidney cortex by reverse transcription-PCR followed by sequencing of a 8 26-bp cDNA fragment and by immunoblotting using two different antibodies. H uman MRP2 was localized to the apical brush-border membrane domain of proxi mal tubules by double and triple immunofluorescence microscopy including la ser scanning microscopy. The expression of MRP2 in renal cell carcinoma was studied by reverse trans cription-PCR and immunoblotting in samples from patients undergoing tumor-n ephrectomy without prior chemotherapy. Clear-cell carcinomas, originating f rom the proximal tubule epithelium, expressed MRP2 in 95% (18 of 19) of cas es. Immunofluorescence microscopy of MRP2 in clear-cell carcinoma showed a lack of a distinct apical-to-basolateral tumor cell polarity and an additio nal localization of MRP2 on intracellular membranes. MRP2, the first cloned ATP-dependent export pump for anionic conjugates detected in human kidney, may be involved in renal excretion of various anionic endogenous substance s, xenobiotics, and cytotoxic drugs. This conjugate-transporting ATPase enc oded by the MRP2 gene has a similar substrate specificity as the multidrug resistance protein MRP1, and may contribute to the multidrug resistance of renal clear-cell carcinomas.