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
JournalAmerican Journal of Physiology - Cell Physiology
Volume279
Issue number5 48-5
StatePublished - 2000

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Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-Kinases
Extremities
Vasopressins
Signal transduction
Chemical activation
Signal Transduction
Kidney Medulla
8-Bromo Cyclic Adenosine Monophosphate
Sodium-Hydrogen Antiporter
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Arginine Vasopressin
Colforsin
Rats
Tissue
Membranes
Plasmas

Keywords

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

ASJC Scopus subject areas

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

Cite this

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title = "Hyposmolality stimulates Na+/H+ exchange and HCO3/- absorption in thick ascending limb via PI 3-kinase",
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.",
keywords = "Adenosine 3',5'-cyclic monophosphate, Hyperosmolality, Phosphatidylinositol 3-kinase, Signal transduction",
author = "Good, {David W.} and {Di Mari}, {John F.} and Watts, {Bruns A.}",
year = "2000",
language = "English",
volume = "279",
journal = "American Journal of Physiology - Endocrinology and Metabolism",
issn = "0193-1849",
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TY - JOUR

T1 - Hyposmolality stimulates Na+/H+ exchange and HCO3/- absorption in thick ascending limb via PI 3-kinase

AU - Good, David W.

AU - Di Mari, John F.

AU - Watts, Bruns A.

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

KW - Adenosine 3',5'-cyclic monophosphate

KW - Hyperosmolality

KW - Phosphatidylinositol 3-kinase

KW - Signal transduction

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M3 - Article

VL - 279

JO - American Journal of Physiology - Endocrinology and Metabolism

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