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Involvement of guanylyl cyclase and cGMP in the regulation of Mrp2-mediated transport in the proximal tubule

¹Department of Pharmacology and Toxicology, University Medical Center Nijmegen, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands; ³Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina 27709; and ²Mount Desert Island Biological Laboratory, Salisbury Cove, Maine 04672

Submitted 16 December 2003 ; accepted in final form 12 February 2004

In killifish renal proximal tubules, endothelin-1 (ET-1), acting through a basolateral ET_B receptor, nitric oxide synthase (NOS), and PKC, decreases cell-to-lumen organic anion transport mediated by the multidrug resistance protein isoform 2 (Mrp2). In the present study, we examined the roles of guanylyl cyclase and cGMP in ET signaling to Mrp2. Using confocal microscopy and quantitative image analysis to measure Mrp2-mediated transport of the fluorescent drug fluorescein methotrexate (FL-MTX), we found that oxadiazole quinoxalin (ODQ), an inhibitor of NO-sensitive guanylyl cyclase, blocked ET-1 signaling. ODQ was also effective when signaling was initiated by nephrotoxicants (gentamicin, amikacin, diatrizoate, HgCl₂, and CdCl₂), which appear to stimulate ET release from the tubules themselves. ODQ blocked the effects of the NO donor sodium nitroprusside but not of the phorbol ester that activates PKC. Exposing tubules to 8-bromo-cGMP (8-BrcGMP), a cell-permeable cGMP analog, decreased luminal FL-MTX accumulation. This effect was abolished by bisindoylmaleimide (BIM), a PKC inhibitor, but not by N^G-methyl-L-arginine, a NOS inhibitor. Together, these data indicate that ET regulation of Mrp2 involves activation of guanylyl cyclase and generation of cGMP. Signaling by cGMP follows NO release and precedes PKC activation.

endothelin signaling; protein kianse C; xenobiotic transport

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