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Acid sensing in renal epithelial cells
Stephen L. Gluck
Division of Nephrology, UCSF, San Francisco, California, USA.
The kidney adjusts net acid excretion to match production with exquisite
precision, despite little or no change in the plasma bicarbonate concen-
tration. The acid-sensing pathway that signals the kidney to increase acid
secretion involves activation of the proto-oncogene c-Src. A new study in
this issue shows that proline-rich tyrosine kinase 2 (Pyk2) is responsible for
acid-induced activation of c-Src and is essential for acid sensing in renal epi-
thelial cells (see the related article beginning on page 1782). The findings
implicate a broader role for Pyk2 in acid-base homeostasis in bone and other
tissues beyond the kidney.
Although the principal product of metabo-
lism in mammalian cells is the volatile acid
carbon dioxide, humans on a typical West-
ern diet produce about 70 millimoles of
nonvolatile acid per day. Remarkably, vary-
ing metabolic acid production over a range
of 0–150 millimoles is accompanied by a
matching increase in net acid excretion by
the kidney with a change of only 1 mM in
plasma bicarbonate concentration (1). The
adaptive responses that enable the kidney
to increase net acid excretion in response to
increased acid generation have been stud-
ied extensively in animal models of meta-
bolic acidosis. In the proximal tubule, aci-
dosis increases the activity of luminal and
basolateral proteins involved in bicarbon-
ate transport (2, 3), ammonia generation
(4), and the reabsorption and metabolism
of citrate (5). In the collecting duct, acido-
sis suppresses bicarbonate secretion (6) and
stimulates recruitment of proton pumps
to the luminal membrane of intercalated
cells (7). Of the acid-base transporters in
the proximal tubule, the luminal sodium/
hydrogen exchanger 3 (NHE3) has a promi-
nent role, and the mechanism by which its
activity increases during metabolic acidosis
has been examined in some detail. Meta-
bolic acidosis acutely increases the kinetic
activity of NHE3 through direct pH effects
and by phosphorylation (8), while chronic
acidosis increases the number of NHE3
kinetics cannot account
for precise pH sensing
How does the kidney “know” to adjust net
acid excretion with such precision with only
minimal changes in plasma bicarbonate con-
centration? Available data in the physiology
literature suggests that transporter kinetics
alone cannot account for this degree of sen-
sitivity. In the proximal tubule, a reduction
in extracellular bicarbonate induces a fall
in intracellular pH, which directly activates
the sodium/hydrogen exchanger through
an intracellular pH regulatory site (10).
This requires a change in intracellular pH
of about 0.1 to achieve a 50% increase in the
rate of transport or an approximately 5%
change in the rate of transport in response
to a change in extracellular bicarbonate
concentration of 1 mM. Both the luminal
vacuolar H+-ATPase and the basolateral
sodium bicarbonate cotransporter in the
proximal tubule are even less responsive to
changes in intracellular pH (11–13). This
suggests that a bicarbonate (or pH) sensor
that can amplify luminal proton secretion
must be present.
Nonstandard abbreviations used: FAK, focal adhe-
sion kinase; NHE3, sodium/hydrogen exchanger 3;
OKP, opossum kidney clone P; Pyk2, proline-rich tyro-
sine kinase 2.
Conflict of interest: The author has declared that no
conflict of interest exists.
Citation for this article: J. Clin. Invest. 114:1696–1699