TY - JOUR
T1 - Feedback inhibition of aldose reductase gene expression in rat renal medulla. Galactitol accumulation enzyme reduces mRNA levels and depletes cellular inositol content
AU - Bondy, C.
AU - Cowley, B. D.
AU - Lightman, S. L.
AU - Kador, P. F.
PY - 1990
Y1 - 1990
N2 - Aldose reductase (AR) is an enzyme responsible for converting glucose into sorbitol and galactose into galactitol. In the renal inner medulla, where sorbitol production plays a role in cellular osmoregulation, AR gene expression has been shown to be osmotically regulated. The present study examined the effects of the accumulation of the AR end product, galactitol, induced by galactose feeding, on AR gene expression and on the balance of other cellular osmolytes, including inositol, in the renal medulla. To differentiate between the effects of excess substrate, product, and intervening osmotic factors, rats were fed either control, galactose, galactose and sorbinil (and AR inhibitor), or control plus sorbinil diets. Renal papillae were assayed for AR mRNA, sodium, urea, galactose, galactitol, sorbitol, inositol, and other organic osmolytes. Galactose feeding resulted in a great accumulation of galactitol and reduction in AR mRNA levels in renal papillae. Associated with these changes was a significant depletion of renal papillary sorbitol, inositol, and glycerolphosphocholine. These effects were largely attenuated by sorbinil. The present findings suggest that renal cellular accumulation of the enzyme's polyol product causes downregulation of AR gene expression. Furthermore, our findings suggest that the inositol depletion associated with sorbitol or galactitol accumulation in various cell types during hyperglycemia may be a function of cellular osmoregulation.
AB - Aldose reductase (AR) is an enzyme responsible for converting glucose into sorbitol and galactose into galactitol. In the renal inner medulla, where sorbitol production plays a role in cellular osmoregulation, AR gene expression has been shown to be osmotically regulated. The present study examined the effects of the accumulation of the AR end product, galactitol, induced by galactose feeding, on AR gene expression and on the balance of other cellular osmolytes, including inositol, in the renal medulla. To differentiate between the effects of excess substrate, product, and intervening osmotic factors, rats were fed either control, galactose, galactose and sorbinil (and AR inhibitor), or control plus sorbinil diets. Renal papillae were assayed for AR mRNA, sodium, urea, galactose, galactitol, sorbitol, inositol, and other organic osmolytes. Galactose feeding resulted in a great accumulation of galactitol and reduction in AR mRNA levels in renal papillae. Associated with these changes was a significant depletion of renal papillary sorbitol, inositol, and glycerolphosphocholine. These effects were largely attenuated by sorbinil. The present findings suggest that renal cellular accumulation of the enzyme's polyol product causes downregulation of AR gene expression. Furthermore, our findings suggest that the inositol depletion associated with sorbitol or galactitol accumulation in various cell types during hyperglycemia may be a function of cellular osmoregulation.
KW - aldose reductase
KW - galactitol
KW - galactose
KW - polyol
KW - sorbitol
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U2 - 10.1172/JCI114814
DO - 10.1172/JCI114814
M3 - Article
C2 - 2120282
AN - SCOPUS:0025011250
SN - 0021-9738
VL - 86
SP - 1103
EP - 1108
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -