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3 absorption via distinct pathways
in thick ascending limb
1 Departments of Medicine and Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555; and 2 Howard Hughes Medical Institute, Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
Mitogen-activated protein (MAP) kinases are
activated by osmotic stress in a variety of cells, but
their function and regulation in renal tubules is poorly understood.
The present study was designed to examine the osmotic regulation of MAP
kinases in the medullary thick ascending limb (MTAL) of the rat and to
determine their possible role in the hyperosmotic inhibition of
HCO
3 absorption in this segment.
Tissues from the inner stripe of the outer medulla and microdissected
MTALs were incubated at 37°C in control (290 mosmol/kgH2O) or hyperosmotic (300 mM added mannitol) solution for 15 min. Activities of extracellular
signal-regulated kinase (ERK), c-Jun
NH2-terminal kinase (JNK), and p38
MAP kinase were then measured using immune complex assays.
Hyperosmolality increased p38 MAP kinase activity (2.3-fold) and ERK
activity (2.0-fold) but had no effect on JNK activity (1.1-fold).
Exposure to hyperosmolality for various times showed that the
activation of p38 MAP kinase was rapid (
5 min) and was sustained for
up to 60 min, whereas the activation of ERK was transient (ERK activity peaked at 15 min, then declined to basal levels at 30 min).
Pretreatment with the MAP kinase kinase inhibitor PD98059 (15 µM) blocked the hyperosmotic activation of p38 MAP kinase and ERK but
did not prevent hyperosmotic inhibition of
HCO3 absorption. These results show
that hyperosmolality differentially activates p38 MAP
kinase and ERK in the MTAL. In contrast, we found no evidence for
involvement of JNK in the early response to hyperosmotic stress. Eliminating the activation of p38 MAP kinase and ERK does not prevent
hyperosmotic inhibition of HCO3
absorption, suggesting that hyperosmolality inhibits apical membrane
Na+/H+
exchange (NHE3) activity via a signaling pathway distinct from these
MAP kinase pathways.
osmotic stress; signal transduction; sodium/proton exchange; mitogen-activated protein kinase
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