Mechanism of regulation of Na+ transport by angiotensin II in primary renal cells

Kidney Int. 2000 Jun;57(6):2457-67. doi: 10.1046/j.1523-1755.2000.00104.x.

Abstract

Background: Angiotensin II (Ang II) has a dose-dependent, biphasic effect on the activity of the Na+/H+ antiport system in the renal proximal tubule (RPT). The aim of the present study was to further delineate the signaling pathways involved in Ang II action.

Methods: To examine Ang II signaling, 22Na+ uptake studies were conducted with a primary rabbit RPT cell culture system. The activation of phospholipase A2 (PLA2) was assessed by measuring the release of [3H]-arachidonic acid (AA), and changes in intracellular calcium levels were determined by means of confocal microscopy.

Results: Low dosages of Ang II (<10-10 mol/L) stimulated Na+ uptake, whereas high dosages of Ang II (>10-10 mol/L) inhibited Na+ uptake. Ang II (>10-10 mol/L) also caused an increase in AA release associated with an increase in intracellular calcium. Not only did exogenous AA inhibit Na+ uptake, but two PLA2 inhibitors (mepacrine and AACOCF3) blocked the Ang II-mediated inhibition of Na+ uptake. However, the cytochrome P450-dependent epoxygenase inhibitor econazole also blocked the Ang II-induced inhibition of Na+ uptake. Inhibition of Na+ uptake was obtained by the metabolic product of the epoxygenase 5,6-EET. In turn, the inhibitory effect of 5,6-EET was blocked by indomethacin.

Conclusions: The results indicate the involvement of a calcium-dependent PLA2 in mediating the inhibitory effect of Ang II on Na+ uptake. The AA, which is released following PLA2 activation, acts indirectly, through its own metabolism, via a cytochrome P450 epoxygenase pathway and ultimately cyclooxygenase itself.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Arachidonic Acid / metabolism
  • Biological Transport / drug effects
  • Calcium / physiology
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / metabolism*
  • Male
  • Rabbits
  • Sodium / antagonists & inhibitors*
  • Sodium / pharmacokinetics*

Substances

  • Angiotensin II
  • Arachidonic Acid
  • Sodium
  • Calcium