Parathyroid hormone inhibits Na+-K+-ATPase through a cytochrome P-450 pathway

Carla M. Pedrosa Ribeiro, George R. Dubay, John R. Falck, Lazaro J. Mandel

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

We have previously shown that parathyroid hormone (PTH)-(1-34) or its analogue PTH-(3-34) inhibits proximal tubule (PT) Na+-K+- adenosinetriphosphatase (Na+-K+-ATPase) activity independently of adenosine 3',5'-cyclic monophosphate generation. The present study used PT suspensions to investigate the signaling pathway responsible for this hormonal action. PTH-(1-34) and PTH-(3-34) significantly increased the release of arachidonic acid (AA) compared with control tubules, suggesting activation of phospholipase A2 (PLA2). AA, 10-6 M, mimicked the inhibition of the pump by 10-5 M PTH-(3-34), and together were not additive. Eicosatetraynoic acid, 3 μM, a general inhibitor of AA metabolism, blocked the PTH action. Indomethacin, 10 μM, in inhibitor of AA-dependent cyclooxygenase, did not prevent the PTH action, but 2 μM 7-ethoxyresorufin, a cytochrome P-450 inhibitor, prevented the PTH effect. 20-Hydroxyeicosatetraenoic acid (20- HETE), the main product of P-450 metabolism in PT, inhibited Na+-K+-ATPase activity to the same extent as 10-8 PTH-(3-34), was not additive with PTH, and was maximally inhibitory at 10-7 M. To further investigate the signaling pathway responsible for PTH-activated PLA2, we tested the effect of PTH on cytoplasmic free Ca2+ ([Ca2+](i)). PTH-(1-34), 10-7 M, did not affect [Ca2+](i), although 10-8 M angiotensin II promoted a Ca2+ transient. Treatment of PT with pertussis toxin (PTX) did not prevent the PTH action. We conclude that PTH inhibits PT Na+-K+-ATPase activity by activating a Ca2+- and PTX-insensitive PLA2 involved in an AA-dependent cytochrome P-450 pathway responsible for the generation of 20-HETE, a metabolite with natriuretic properties.

Original languageEnglish (US)
Pages (from-to)F497-F505
JournalAmerican Journal of Physiology - Renal Fluid and Electrolyte Physiology
Volume266
Issue number3 35-3
DOIs
StatePublished - 1994

Keywords

  • 20-hydroxyeicosatetraenoic acid
  • arachidonic acid
  • cytochrome P- 450
  • sodium-potassium-adenosinetriphosphatase

ASJC Scopus subject areas

  • Physiology

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