TRANSCRIPTIONAL REGULATION BY GLUCOCORTICOIDS OF MITOCHONDRIAL OXIDATIVE ENZYME GENES IN THE DEVELOPING RAT-KIDNEY

Mitochondrial fatty acid beta-oxidation plays a major role in providin g the ATP required for reabsorptive processes in the adult rat kidney. However, the molecular mechanisms and signals involved in induction o f the enzymes of fatty acid oxidation during development in this and o ther organs are unknown. We therefore studied the changes in the stead y-state levels of mRNA encoding medium-chain acyl-CoA dehydrogenase (M CAD), which catalyses the initial step in mitochondrial fatty acid bet a-oxidation, in the rat kidney cortex and medulla between postnatal da ys 10 and 30. Furthermore, we investigated whether the expression of M CAD and of mitochondrial malate dehydrogenase (mMDH), a key enzyme in the tricarboxylic acid cycle, might be co-ordinately regulated by circ ulating glucocorticoids in the immature kidney during development. In the cortex, the levels of MCAD mRNA rose 4-fold between day 10 and day 21. and then decreased from day 21 to day 30. In the medulla a postna tal increase in the concentration of MCAD mRNA (8-fold) was observed d uring the same period. Adrenalectomy prevented the 16-21-day developme ntal increases in MCAD and mMDH mRNA levels in the cortex and medulla; these could be restored by dexamethasone treatment. A single injectio n of dexamethasone into 10-day-old rats led to a rise in MCAD and mMDH mRNA levels in the renal cortex due to stimulation of gene transcript ion, as shown by nuclear run-on assays. Therefore MCAD and mMDH gene e xpression is tightly regulated at the transcriptional level by develop mental changes in circulating glucocorticoid levels. These hormones mi ght thus represent a good candidate as a co-ordinating factor in the e xpression of nuclear genes encoding mitochondrial enzymes in the kidne y during postnatal development.