Developmental expression and function of aldehyde reductase in proximal tubules of the kidney

Abstract

Aldehyde reductase reduces a wide variety of toxic and physiological aldehydes with a marked preference for negatively charged substrates such as glucuronate. Reduction of glucuronate to gulonate is a step in inositol catabolism, a process specific to the kidney cortex. Administration of the aldehyde reductase inhibitor AL-1576 to mice increases urinary output of glucuronate and decreases output of vitamin C. Aldehyde reductase mRNA with a 319-bp 5'-untranslated region is expressed ubiquitously in murine tissues. A new isoform with a short 64-bp 5'-untranslated region is found predominantly in the kidney, resulting in 10-fold higher enzymatic activity observed in this organ compared with other tissues. A moderate level of the new transcript is found in liver, intestine, and stomach, whereas brain, heart, lung, spleen, ovary, and testis have low to insignificant levels. The short transcript is absent during embryonic development and is first observed in the murine kidney on postnatal day 6. The abundance of the short transcript and enzyme activity increase sigmoidally with age; the sharpest increase occurs during the third week of life. As shown by immunohistochemistry, aldehyde reductase expression is limited to the proximal tubules and parietal epithelium of Bowman's capsule. In the mouse, the intensity of staining in tubules increases with age, suggesting that induction of aldehyde reductase expression is part of renal tubular maturation. The human kidney also exhibits proximal tubular localization and the two mRNA transcripts of aldehyde reductase. Immunoreactive protein is present in the 9-wk-old fetal kidney, indicating that the induction of aldehyde reductase in humans occurs early in development.