Intracellular betaine substitutes for sorbitol in protecting renal medullary cells from hypertonicity

1991 ◽  
Vol 260 (4) ◽  
pp. F494-F497 ◽  
Author(s):  
T. Moriyama ◽  
A. Garcia-Perez ◽  
A. D. Olson ◽  
M. B. Burg
Keyword(s):  
Aldose Reductase ◽  
Reductase Activity ◽  
Organic Osmolytes ◽  
Cloning Efficiency ◽  
Hypertonic Medium ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors ◽  
Nacl Concentration ◽  
Medullary Cells

Renal medullary cells are normally exposed to a variably high extracellular NaCl concentration. They compensate by accumulating large amounts of organic osmolytes, including sorbitol and betaine. The sorbitol is synthesized from glucose, catalyzed by aldose reductase. Previously, inhibition of aldose reductase activity was noted to greatly reduce renal medullary cell survival and growth (measured by cloning efficiency) in tissue cultures of renal medullary cells in hypertonic medium. In contrast, inhibition of aldose reductase and renal medullary sorbitol accumulation is not associated with kidney damage in vivo. In the present experiments we find that addition of betaine to the medium, and its resultant uptake by the cells, largely replaces the decrease in sorbitol caused by aldose reductase inhibitors and restores the cloning efficiency. We presume that in vivo uptake of betaine by renal medullary cells similarly protects them from harm when aldose reductase inhibitors lower sorbitol. The results also demonstrate that one organic osmolyte can substitute for another in protecting cells from hypertonicity, consistent with the compatible osmolytes hypothesis.

Factors affecting the ratio of different organic osmolytes in renal medullary cells

1990 ◽  
Vol 259 (5) ◽  
pp. F847-F858 ◽  
Author(s):  
T. Moriyama ◽  
A. Garcia-Perez ◽  
M. B. Burg
Keyword(s):  
Tissue Culture ◽  
Aldose Reductase ◽  
Glucose Concentration ◽  
Reductase Activity ◽  
Renal Medulla ◽  
Organic Osmolytes ◽  
Factors Affecting ◽  
High Concentrations ◽  
Medullary Cells

Renal medullary cells contain high concentrations of sorbitol, inositol, glycerophosphorylcholine (GPC), and betaine, which balance the variably high osmolality of extracellular NaCl. We found that PAP-HT25 (rabbit renal medullary) cells in tissue culture increase their content of all four when medium osmolality is increased by adding NaCl and urea. However, this requires that betaine be added to medium in addition to customary constituents. Some factors affecting the mix of organic osmolytes in these cells during hypertonicity are as follows. 1) Urea in medium increases cell GPC and tends to decrease others, particularly betaine. 2) With small increases in medium NaCl, intracellular inositol is highest, whereas sorbitol predominates with large NaCl increases. 3) When osmolality is suddenly decreased, these four organic osmolytes exit rapidly from cells, but in differing relative amounts (betaine much greater than sorbitol greater than inositol much greater than GPC). 4) Altering cell betaine levels (by varying betaine in medium) causes reciprocal changes in cell sorbitol (by affecting aldose reductase activity) and vice versa, whereas inositol and GPC are less affected. 5) Raising medium glucose concentration (from which sorbitol is synthesized) increases cell sorbitol and decreases cell inositol and betaine. 6) Decreasing the amount of GPC in cells (by removing choline from medium) causes small changes in betaine and sorbitol, but not in inositol. Changing the amount of inositol does not affect the others. Similar interrelations may operate in vivo to vary the mix of organic osmolytes in renal medulla.

Effects of NaCl, glucose, and aldose reductase inhibitors on cloning efficiency of renal medullary cells

1990 ◽  
Vol 258 (1) ◽  
pp. C156-C163 ◽  
Author(s):  
P. H. Yancey ◽  
M. B. Burg ◽  
S. M. Bagnasco
Keyword(s):  
Aldose Reductase ◽  
High Glucose ◽  
Reductase Activity ◽  
Cloning Efficiency ◽  
Glucose Levels ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors ◽  
Colony Forming Efficiency ◽  
Forming Efficiency ◽  
Osmotic Balance

To analyze the effects of sorbitol accumulation on the survival and growth of epithelial cells from rabbit renal inner medulla, cloning efficiency (an index of cell viability) was measured at normal and high glucose and NaCl concentrations and when sorbitol accumulation was prevented by Tolrestat and Sorbinil, which inhibit aldose reductase. With PAP-HT25 cells grown to near confluence, high NaCl increases aldose reductase activity, causing enough rise in cell sorbitol concentration to balance most of the increased osmolality of the high extracellular NaCl. Inhibition of aldose reductase prevents both the increased enzyme activity and sorbitol accumulation in a dose-related manner. Paralleling this, colony-forming efficiency is not affected by the inhibitors at a normal NaCl concentration but is greatly reduced when extracellular NaCl is high. On the other hand, high glucose levels, as occur in diabetes, increase sorbitol content well above the concentration required for osmotic balance and inhibit colony-forming efficiency. Under those conditions, aldose reductase inhibitors lower cell sorbitol and reverse (at 300-350 mosmol/kgH2O) or reduce (at 500-550 mosmol/kgH2O) the decrease in colony-forming efficiency caused by high glucose. Thus sorbitol accumulation is necessary for osmoregulation when induced by high osmolality but is harmful when induced by high glucose.

Spirohydantoin derivatives of thiopyrano[2,3-b]pyridin-4(4H)-one as potent in vitro and in vivo aldose reductase inhibitors

2005 ◽  
Vol 13 (2) ◽  
pp. 491-499 ◽  
Author(s):  
Federico Da Settimo ◽  
Giampaolo Primofiore ◽  
Concettina La Motta ◽  
Silvia Salerno ◽  
Ettore Novellino ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors ◽  
Derivatives Of

Osmoregulation by slow changes in aldose reductase and rapid changes in sorbitol flux

1988 ◽  
Vol 254 (6) ◽  
pp. C788-C792 ◽  
Author(s):  
S. M. Bagnasco ◽  
H. R. Murphy ◽  
J. J. Bedford ◽  
M. B. Burg
Keyword(s):  
Epithelial Cells ◽  
Aldose Reductase ◽  
Cell Protein ◽  
Organic Osmolytes ◽  
Continuous Line ◽  
Nacl Concentration ◽  
Rapid Changes ◽  
Low Levels ◽  
Medullary Cells ◽  
In Cells

Renal medullary extracellular NaCl concentration is high during antidiuresis. To compensate, the cells accumulate large amounts of nonperturbing, osmotically active solutes (organic “osmolytes”), including sorbitol. GRB-PAP1 is a continuous line of epithelial cells from rabbit inner medulla. These cells accumulate sorbitol when medium NaCl concentration is elevated. The accumulation involves increase in aldose reductase, which catalyzes production of sorbitol from glucose. The purpose of the present study was to investigate control of cell sorbitol once aldose reductase was induced. We measured cell sorbitol, cell-to-medium sorbitol flux, and aldose reductase in cells grown in medium made hyperosmotic (600 mosmol/kg) with added NaCl and at intervals after medium osmolality was reduced to 300 mosmol/kg. In the hyperosmotic medium, cell sorbitol averaged 990 mmol/kg protein (approximately 260 mM), and its flux into the medium was 740 mmol.kg cell protein-1.day-1 (permeability less than 2 X 10(-9) cm/s). Within 5 min after return to isosmotic medium, sorbitol efflux increased greater than 150-fold. By the end of 1 day, cell sorbitol fell 77% but aldose reductase decreased only 10%. Aldose reductase then fell slowly to low levels over 2 wk. Thus renal medullary cells, chronically adapted to high NaCl, reduced their sorbitol level on return to isosmotic conditions by at least two mechanisms: 1) rapid increase in sorbitol flux into the medium, and 2) slow changes in the amount of aldose reductase.

Renal medullary organic osmolytes

1991 ◽  
Vol 71 (4) ◽  
pp. 1081-1115 ◽  
Author(s):  
A. Garcia-Perez ◽  
M. B. Burg
Keyword(s):  
Aldose Reductase ◽  
Renal Medulla ◽  
Organic Osmolytes ◽  
Organic Osmolyte ◽  
Concentrating Mechanism ◽  
Nacl Concentration ◽  
Survival And Growth ◽  
Harmful Effects ◽  
Medullary Cells

Sorbitol, inositol, GPC, and betaine are the predominant organic osmolytes in renal medullary cells. They protect the cells from harmful effects of the high interstitial NaCl and urea concentrations that occur normally in the renal medulla with operation of the urinary concentrating mechanism. Their levels correlate with extracellular NaCl concentration and, in the case of GPC, also with urea. Sorbitol is synthesized from glucose in a reaction catalyzed by aldose reductase. Inositol and betaine are transported into the cell. Glycerophosphorylcholine synthesis is dependent on choline. The transcription of aldose reductase and the transport of betaine and inositol are regulated, dependent on the degree of hypertonicity. Normal organic osmolyte regulation contributes to the survival and growth of medullary cells in their hyperosmolal environment, and defective regulation can damage them.

In vivo activities of aldose reductase inhibitors having a 1-(arylsulfonyl)hydantoin structure

1990 ◽  
Vol 40 (2) ◽  
pp. 303-307 ◽  
Author(s):  
Ichitomo Miwa ◽  
Masuharu Hirano ◽  
Motoya Kanbara ◽  
Jun Okuda
Keyword(s):  
Aldose Reductase ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors
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