20-HETE mediates the effect of parathyroid hormone and protein kinase C on renal phosphate transport.
Parathyroid hormone (PTH) is a major inhibitor of renal proximal tubule (PT) sodium-dependent phosphate (Na+-Pi) cotransport. PTH is thought to exert its effect on Pi transport in the PT via the protein kinase A (PKA) and C (PKC) intracellular signalling pathways. PKC-dependent phosphorylation of phospholipase A2 stimulates arachidonic acid (AA) release, the latter a potent inhibitor of Pi transport. In turn, AA is metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE) in the PT. In addition, 20-HETE production is stimulated by PTH. We therefore explored the possibility that 20-HETE may mediate the PTH/PKC inhibition of renal Na+-Pi cotransport. To this end, we tested the effect of 20-HETE on Na+-Pi cotransport in proximal tubule-like cells. Exposure of opossum kidney (OK) cells for 4 h to 20-HETE (10(-7) M) decreased Na+-dependent uptake of 32Pi (from 0.26 +/- 0.02 to 0.19 +/- 0.01 nmol/mg protein.min) by approximately 25% (P < 0.001). The inhibition was due to a reduction in Vmax. 20-HETE had no significant effect on either the apical amiloride-sensitive and insensitive 22Na uptakes or on basolateral ouabain-sensitive 86Rb uptake, and was specific for Pi. These results indicate that 20-HETE specifically inhibits Na+-dependent Pi transport in OK cells and that it may be a mediator of PTH action in the PT.
Silverstein
D M
DM
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Barac-Nieto
M
M
Falck
J R
JR
Spitzer
A
A
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D010281:Parathyroid Hormone / Q000378:metabolism*; D010710:Phosphates / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D012964:Sodium / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters
D002352:Carrier Proteins; D006893:Hydroxyeicosatetraenoic Acids; D010281:Parathyroid Hormone; D010710:Phosphates; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D012964:Sodium; D011493:Protein Kinase C