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Abstract
The renal response to metabolic acidosis is mediated, in part, by increased expression
of the genes encoding key enzymes of glutamine catabolism and various ion transporters
that contribute to the increased synthesis and excretion of ammonium ions and the
net production and release of bicarbonate ions. The resulting adaptations facilitate
the excretion of acid and partially restore systemic acid-base balance. Much of this
response may be mediated by selective stabilization of the mRNAs that encode the responsive
proteins. For example, the glutaminase mRNA contains a direct repeat of 8-nt AU sequences
that function as a pH-response element (pHRE). This element is both necessary and
sufficient to impart a pH-responsive stabilization to chimeric mRNAs. The pHRE also
binds multiple RNA-binding proteins, including zeta-crystallin (zeta-cryst), AU-factor
1 (AUF1), and HuR. The onset of acidosis initiates an endoplasmic reticulum (ER)-stress
response that leads to the formation of cytoplasmic stress granules. zeta-cryst is
transiently recruited to the stress granules, and concurrently, HuR is translocated
from the nucleus to the cytoplasm. On the basis of the cumulative data, a mechanism
for the stabilization of selective mRNAs is proposed. This hypothesis suggests multiple
experiments that should define better how cells in the kidney sense very slight changes
in intracellular pH and mediate this essential adaptive response.