Hyposmolality stimulates Na+/H+ exchange and HCO3/- absorption in thick ascending limb via PI 3-kinase

David W. Good, John F. Di Mari, Bruns A. Watts

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Abstract

The signal transduction mechanisms that mediate osmotic regulation of Na+/H+ exchange are not understood. Recently we demonstrated that hyposmolality increases HCO3/- absorption in the renal medullary thick ascending limb (MTAL) through stimulation of the apical membrane Na+/H+ exchanger NHE3. To investigate the mechanism of this stimulation, MTALs from rats were isolated and perfused in vitro with 25 mM HCO3/- containing solutions. The phosphatidylinositol 3-kinase (PI 3-K) inhibitors wortmannin (100 nM) and LY-294002 (20 μM) blocked completely the stimulation of HCO3/- absorption by hyposmolality. In tissue strips dissected from the inner stripe of the outer medulla, the region of the kidney highly enriched in MTALs, hyposmolality increased PI 3-K activity 2.2-fold. Wortmannin blocked the hyposmolality-induced PI 3-K activation. Further studies examined the interaction between hyposmolality and vasopressin, which inhibits HCO3/- absorption in the MTAL via cAMP and often is involved in the development of plasma hyposmolality in clinical disorders. Pretreatment with arginine vasopressin, forskolin, or 8-bromo-cAMP abolished hyposmotic stimulation of HCO3/- absorption, due to an effect of cAMP to inhibit hyposmolality-induced activation of PI 3-K. In contrast to their effects to block stimulation by hyposmolality, PI 3-K inhibitors and vasopressin have no effect on inhibition of apical Na+/H+ exchange (NHE3) and HCO3/- absorption by hyperosmolality. These results indicate that hyposmolality increases NHE3 activity and HCO3/- absorption in the MTAL through activation of a PI 3-K-dependent pathway that is inhibited by vasopressin and cAMP. Hyposmotic stimulation and hyperosmotic inhibition of NHE3 are mediated through different signal transduction mechanisms.

Original languageEnglish (US)
Pages (from-to)C1443-C1454
JournalAmerican Journal of Physiology - Cell Physiology
Volume279
Issue number5 48-5
StatePublished - Dec 7 2000

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Keywords

  • Adenosine 3',5'-cyclic monophosphate
  • Hyperosmolality
  • Phosphatidylinositol 3-kinase
  • Signal transduction

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology
  • Physiology (medical)

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