Developmental and Physiological Regulation of Aldose Reductase mRNA Expression in Renal Medulla

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Abstract
Atdose reductase (AR), an enzyme that catalyzes the conversion of glucose to sorbitol, has been implicated in the pathogenesis of many of the complications of diabetes mellitus, but its normal physiological function in various tissues remains uncertain. It has been suggested that in the kidney, sorbitol production may be an important cellular protection against medullary interstitial hypertonicity. Using in situ and Northern hybridization analyses, we found that at the time of birth, AR mRNA expression in the kidney was very low and seen only in the papilla. By 12 days of age, at about the time a corticopapillary osmotic gradient and the capacity for urinary concentration have developed, a striking increase in renal AR mRNA levels was seen. It was confined to the inner medulla and was characterized by a dramatic gradient of expression paralleling the corticopapillary osmotic gradient. Levels of expression were somewhat lower in adults, but showed the same inner medullary boundary and gradient. Under these hybridization and exposure conditions, no AR transcripts were detected in the outer medulla or cortex. Homozygous Brattleboro rats with congenital diabetes insipidus have relatively dilute corticopapillary osmotic gradients, and their level of medullary AR mRNA was significantly lower than that of controls. Conversely, normal rats made hyperosmotic and, hence, antidiuretic by salt loading showed a large increase in medullary AR mRNA. These changes in renal medullary AR gene expression in correlation with changes in medullary tonicity support the hypothesis that renal AR plays a role in cellular adaption to osmotic stress and suggest that local medullary osmolarity may regulate the level of AR gene expression.