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absorption in thick
ascending limb via PI 3-kinase
Deparments of Medicine and Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555
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.
signal transduction; adenosine 3',5'-cyclic monophosphate; phosphatidylinositol 3-kinase; hyperosmolality
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