Molecular basis for osmoregulation of organic osmolytes in renal medullary cells.
Renal medullary cells are naturally exposed to extremely high and variable interstitial concentrations of NaCl and urea, consequent to operation of the urinary concentrating mechanism. They respond by accumulating large and variable amounts of sorbitol, glycerophosphocholine (GPC), glycine betaine (betaine), myo-inositol (inositol), and taurine both in vivo and in cell cultures. Sorbitol is synthesized from glucose, catalyzed by aldose reductase. Hypertonicity increases aldose reductase activity by raising this enzyme's transcription, mRNA level, and translation, and thereby increases production of sorbitol. GPC is synthesized from choline via phosphatidylcholine. A combination of high NaCl plus urea does not increase GPC synthesis, but does reduce its degradation by inhibiting GPC:choline phosphodiesterase. Betaine, inositol and taurine are taken up into the cells, each by a different sodium-dependent transporter. Hypertonicity increases mRNAs of all three transporters. This is due to increased transcription (at least of the inositol and betaine transporters). The eventual result is greater betaine, inositol and taurine uptake and accumulation. Osmoregulation of net sorbitol and GPC synthesis and of betaine, inositol and taurine transport is slow, requiring hours to days. However, following an acute fall in tonicity, these organic osmolytes exit from the cells within minutes, via specialized efflux mechanisms. As demonstrated by cloning efficiency studies, renal cell survival and growth following hypertonicity depend on the sum of all organic osmolytes that are accumulated; altering one experimentally changes the others to maintain a nearly constant total. Methylamine accumulation protects these cells against high urea; the methylamine that is preferentially accumulated in response to high urea is GPC.
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National Institutes of Health, Bethesda, Maryland 20892.
D000818:Animals; D001622:Betaine / Q000378:metabolism; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D007294:Inositol / Q000378:metabolism; D007679:Kidney Medulla / Q000166:cytology / Q000502:physiology*; D010713:Phosphatidylcholines / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013654:Taurine / Q000378:metabolism; D014882:Water-Electrolyte Balance / Q000502:physiology*
D010713:Phosphatidylcholines; D013654:Taurine; D001622:Betaine; D007294:Inositol; D013012:Sorbitol