Angiotensin II inhibits HCO3/- absorption via a cytochrome P-450- dependent pathway in MTAL

David W. Good, Thampi George, Donna H. Wang

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Abstract

The role of ANG II in the regulation of ion reabsorption by the renal thick ascending limb is poorly understood. Here, we demonstrate that ANG II (10-8 M in the bath) inhibits HCO3/- absorption by 40% in the isolated, perfused medullary thick ascending limb (MTAL) of the rat. The inhibition by ANG II was abolished by pretreatment with eicosatetraynoic acid (10 μM), a general inhibitor of arachidonic acid metabolism, or 17-octadecynoic acid (10 μM), a highly selective inhibitor of cytochrome P-450 pathways. Bath addition of 20-hydroxyeicosatetraenoic acid (20-HETE; 10-8 M), the major P- 450 metabolite in the MTAL, inhibited HCO3/- absorption, whereas pretreatment with 20-HETE prevented the inhibition by ANG II. The addition of 15-HETE (10-8 M) to the bath had no effect on HCO3/- absorption. The inhibition of HCO3/- absorption by ANG II was reduced by >50% in the presence of the tyrosine kinase inhibitors genistein (7 μM) or herbimycin A (1 μM). We found no role for cAMP, protein kinase C, or NO in the inhibition by ANG II. However, addition of the exogenous NO donor S-nitroso-N- acetylpenicillamine (SNAP; 10 μM) or the NO synthase (NOS) substrate L- arginine (1 mM) to the bath stimulated HCO3/- absorption by 35%, suggesting that NO directly regulates MTAL HCO3/- absorption. Addition of 10-11 to 10-10 M ANG II to the bath did not affect HCO3/- absorption. We conclude that ANG II inhibits HCO3/- absorption in the MTAL via a cytochrome P-450- dependent signaling pathway, most likely involving the production of 20- HETE. Tyrosine kinase pathways also appear to play a role in the ANG II- induced transport inhibition. The inhibition of HCO3/- absorption by ANG II in the MTAL may play a key role in the ability of the kidney to regulate sodium balance and extracellular fluid volume independently of acid-base balance.

Original languageEnglish (US)
Pages (from-to)F726-F736
JournalAmerican Journal of Physiology - Renal Physiology
Volume276
Issue number5 45-5
StatePublished - May 1 1999

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Keywords

  • 20-hydroxyeicosatetraenoic acid
  • Acid-base regulation
  • Nitric oxide
  • Signal transduction
  • Tyrosine kinases

ASJC Scopus subject areas

  • Physiology
  • Urology

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