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Renal Cellular and
Molecular Biology Section
Maurice B Burg, MD, Principal
Investigator
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DNA damage exists in
mouse inner medullas in
vivo under the normal
condition of high NaCl
and urea.
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more. |
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Our focus has been on the
mechanisms by which cells in the
renal medulla withstand the high
concentrations of salt (NaCl)
and urea that occur there when
the kidney produces concentrated
urine and that are much higher
than elsewhere in the body. We
initially identified some
organic osmolytes (sorbitol,
glycine betaine,
glycerophosphocholine (GPC) and
myo-inositol) that renal
medullary cells accumulate
during antidiuresis. Then, we
established tissue culture
models to elucidate the
protective function of the
osmolytes and the mechanisms by
which they are accumulated
(reviewed in Garcia-Perez, et
al, 1991 ).
We discovered the biochemical
mechanisms by which the organic
osmolytes are accumulated. High
NaCl increases synthesis of
sorbitol from glucose by
increasing the amount of the
enzyme, aldose reductase, and
increases transport of glycine
betaine and myo-inositol into
the cells by increasing the
number of transporters. The
transcription of the aldose
reductase and transporter genes
is osmotically regulated. We
identified an osmotic response
element (ORE) in the aldose
reductase gene and similar
elements have been identified in
the transporter genes.
Currently, we are studying a
transcription factor, TonEBP,
whose binding to the ORE and
whose transactivating activity
are increased by hypertonicity,
signaled by protein kinases,
including PKA (Ferraris, et al,
2002).
Our ongoing work also
concerns the genomic stress that
can occur at extremes of high
NaCl or urea and result in cell
cycle arrest and apoptosis.
Recent findings are that high
NaCl causes DNA damage and
impairs DNA repair, not only in
cell culture, but also in vivo (Dmitrieva,
et al, 2003). Moreover, the
damage is less if the cells are
not proliferating rapidly
(Zhang, et al, 2002) and if the
changes in NaCl and urea
concentration are slow (Cai, et
al, 2002, 2004), as occurs in
the renal inner medulla in vivo. |
