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J Physiol 558.

1 (2004) p 3 3
PERSPECTI VES
Drying and salting send different
messages
Joan D. Ferraris and Maurice B. Burg
Laboratory of Kidney and Electrolyte
Metabolism, National Heart Lung Blood
Institute, National Institutes of Health, 10
Center Drive MSC 1603, Bethesda, MD
20892-1603, USA
Email: ferraris@nhlbi.nih.gov
How do cells cope with drying or exposure
to excessive salt concentrations? In plants,
adaptation to desiccation and adaptation to
salt stress can involve the same mechanism
in which increased transcription of betaine
aldehyde dehydrogenase leads to synthesis of the
compatible organic osmolyte, glycine betaine
(Kotchoni & Bartels, 2003). In this issue of
The Journal of Physiology, Huang & Tunnacliffe
(2004) have now examined the possibility that
a common mechanism exists in mammalian
cells by comparing their responses to water
loss when this is caused by hypertonicity versus
desiccation. Little is known about the adaptive
response to desiccation in mammalian cells.
The present studies not only provide lessons
about the signalling systems involved, but also
raise the possibility that mammalian cells could
be dried in a viable form, which could have
signicant applications in both medicine and
basic research.
In mammalian renal cells, responses to
hypertonicity induced by high concentrations
of NaCl or non-ionic impermeant solutes such
as rafnose involve adaptive accumulation
of several compatible organic osmolytes,
including sorbitol, betaine and inositol (Burg
et al. 1997). Accumulation of these solutes
occurs as a result of increased transcription
of aldose reductase (AR, which catalyses
the conversion of glucose to sorbitol), the
betaine -aminobutyric acid transporter
(BGT1) and the sodiummyo-inositol co-
transporter (SMIT), respectively, all of which
are up-regulated by a transcription factor
called TonEBP/OREBP (for tonicity-responsive
enhancer/osmotic response element-binding
protein; reviewed by Irarrazabal et al. 2004).
It is not entirely clear what initiates hyper-
tonicity-induced activation of TonEBP/OREBP.
Hypertonicity shrinks cells and increases
intracellular ionic strength, andprevious studies
have attempted to distinguish the relative
importance of these two stimuli. Huang &
Tunnacliffe start with the assumption that
desiccation also should have both effects, and
therefore should lead to adaptive accumulation
of compatible osmolytes. Interestingly, they
nd that hypertonicity (caused by high
concentrations of sodium salts or mannitol, but
not KCl or sorbitol) increases AR, BGT1 and
SMIT mRNAs in 293T cells whilst desiccation
does not. The negative result during desiccation
renews the question of whether hypertonicity
activates the adaptive response by cell shrinkage
or increased intracellular ionic strength.
Previous attempts to resolve this question did
not produce a straightforward answer. Thus,
in response to high NaCl or rafnose, with
or without ouabain, AR activity correlates
with cell potassium concentration and even
more strongly with the sum of cell sodium
plus potassium concentration or ionic strength,
but not with cell sodium concentration or
water content alone. The conclusion was
that intracellular ionic strength, rather than
cell volume, is the stimulus (Uchida et al.
1989). Later experiments, in which mRNAs for
TonEBP/OREBP target genes were measured
as an end point, revealed a correlation with
ionic strength but also showed that simply
raising intracellular ionic strength with ouabain
or high KCl is not sufcient to elevate the
mRNAs (Neuhofer et al. 2002). The authors
suggested that cell swelling might have occurred
under those conditions, which could potentially
counteract the effect of increased ionic strength.
Finally, a sufciently slow rise in osmolality
generally results in isovolumetric regulation
in which intracellular ionic strength increases
without cell shrinkage. Under those conditions
AR and BGT1 mRNAs increase greatly,
emphasizing the importance of intracellular
ionic strength (Cai et al. 2004).
Based on their results, Huang & Tunnacliffe
conclude that the stimulus for osmotic
regulation of these genes must involve factors
other than intracellular ionic strength and
cell shrinkage. Why else would the effects
of hypertonicity and desiccation differ so
profoundly? Other factors are also needed to
explain why hypertonicity induced by sodium
salts has effects that are different from those
produced by elevation of KCl or sorbitol. The
authors suggest that sodium concentration, per
se, may be most important. However, this is
unlikely to be a general phenomenon because
the non-ionic, organic solute rafnose is as
effective as NaCl in up-regulating these genes
in other cell types (Burg et al. 1997). We agree
that the osmotic regulation of these genes must
involve factors other than intracellular ionic
strength and cell shrinkage, but disagree that
sodium is key. What might those other factors
be?
We suggest that signals arising from other
effects of hypertonicity affect the activity of
TonEBP/OREBP, adding to or negating the
inuence of ionic strength and cell volume.
Two candidates come from recent observations
that hypertonicity causes DNA damage and
increases reactive oxygen species (ROS),
both in cell culture and in vivo (reviewed in
Zhang et al. 2004). Multiple agents, including
high NaCl, high urea, UV and ionizing
radiation, generate DNA damage and activate
ATM, a DNA damage response protein.
Among these agents, only high NaCl activates
TonEBP/OREBP. The increased activity of
ATM is necessary for full osmotic activation of
TonEBP/OREBP (Irarrazabal et al. 2004). ROS,
which are increased by high NaCl, contribute
to the regulation of transcription factors other
thanTonEBP/OREBP, and we suggest that inthe
context of hypertonicity, ROS may contribute
to the osmotic regulation of TonEBP/OREBP.
Along the same lines, p38 mitogen-activated
protein kinase (MAPK) is known to mediate
many stress signalling pathways, including
activation of TonEBP/OREBP by hypertonicity.
Huang & Tunnacliffe now nd that desiccation
also activates p38, but it does not activate
TonEBP/OREBP. Evidently, activation of
TonEBP/OREBP by p38 requires additional
accompanying signals that desiccation does
not provide. Thus, hypertonicity has multiple
effects andtriggers multiple signallingpathways.
Those signals need to act in concert rather
than individually to cause full activation of
TonEBP/OREBP.
By examining the previously little explored
area of signals arising from desiccation in
mammalian cells and comparing the effects to
those of hypertonicity, Huang & Tunnacliffe
have opened an exciting new area of research.
Their studies shed new light on the under-
studied problem of desiccation in mammalian
cells, and also the extensively studied (but still
incompletely understood) area of signals arising
from hypertonicity.
Burg MB, Kwon ED & K ultz D (1997). Annu Rev
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Cai Q, Ferraris JD & Burg MB (2004).
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Irarrazabal CE, Liu JC, Burg MB & Ferraris JD
(2004). Proc Natl Acad Sci U S A 101,
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Kotchoni SO & Bartels D (2003). Bulg J Plant
Physiol Special Issue, 3751.
Neuhofer W, Woo SK, Na KY, Gr unbein R, Park
WK, Nahm O et al. (2002). Am J Physiol Cell
Physiol 283, C1604C1611.
Uchida S, Garcia-Perez A, Murphy H & Burg M
(1989). Am J Physiol 256, C614C620.
Zhang Z, Dmitrieva NI, Park JH, Levine RL &
Burg MB (2004). Proc Natl Acad Sci U S A
(in press).
C
The Physiological Society. No claim to original US government works. DOI: 10.1113/jphysiol.2004.068064

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