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Endothelins

Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport

¹Department of Animal Physiology, Institute for Neuroscience Faculty of Science, Radboud University Nijmegen, and ²Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences/Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; ³ Mount Desert Island Biological Laboratory, Salisbury Cove, Maine; ⁴Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; ⁵Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; and ⁶Institute of Environmental Systems Biology, Dalian Maritime University, Dalian, China

Submitted 1 December 2005 ; accepted in final form 24 July 2006

The kidney of vertebrates plays a key role in excretion of endogenous waste products and xenobiotics. Active secretion in the proximal nephron is at the basis of this excretion, mediated by carrier proteins including multidrug resistance protein 2 (Mrp2). We previously showed that Mrp2 function is reduced by endothelin-1 (ET-1) through a basolateral B-type receptor, nitric oxide (NO), cGMP, and PKC (Notenboom S, Miller DS, Smits P, Russel FGM, Masereeuw R. Am J Physiol Renal Physiol 282: F458–F464, 2002; Notenboom S, Miller DS, Smits P, Russel FG, Masereeuw R. Am J Physiol Renal Physiol 287: F33–F38, 2004). This pathway was rapidly activated by several nephrotoxicants and appeared to be calcium dependent. In the present study, we studied the effect of the calciotropic hormones parathyroid hormone (PTH), PTH-related protein (PTHrP), and stanniocalcin (STC) to interfere with ET-regulated Mrp2 transport. Like ET-1, PTH reduces Mrp2-mediated transport by 40% in killifish renal proximal tubules. When given in combination, an additive effect was seen, which is partially reversed by the PKC inhibitor calphostin C. Recombinant PTHrP shows a comparable inhibitory effect, which is concentration dependent and additive to the inhibition by ET. STC fully reverses PTHrP-inhibited transport as does a guanylyl cyclase inhibitor. Finally, to confirm PTHrP bioactivity in a homologous assay, we performed immunolocalization and transport studies in sea bream kidney tubules. Mrp2 immunoreactivity was observed in 40% of the tubules and is associated with the brush-border and apical plasma membrane of cells. Both proximal tubules and distal (collecting) tubules express the antigen. A highly significant 40% inhibition of Mrp2-mediated transport was observed with PTHrP in sea bream tubules. In conclusion, ET-regulated Mrp2 transport is influenced by calciotropic hormones and involves PKC and cGMP signaling.

parathyroid hormone; parathyroid hormone-related protein; stanniocalcin; xenobiotic transport; fluorescein-methotrexate; Sparus auratus; gilthead sea bream; Fundulus heteroclitus; killifish

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