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

Author:

Good David W.1,Di Mari John F.1,Watts Bruns A.1

Affiliation:

1. Deparments of Medicine and Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555

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.

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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