THYROID-HORMONE INDUCTION OF ORNITHINE DECARBOXYLASE IN ISCHEMIC ACUTE-RENAL-FAILURE

Thyroid hormone is an important interventional agent shown to be benef icial in a variety of models of acute renal failure (ARF). While its u sefulness is clear, its mechanism of action remains unknown. Although there are a multitude of thyroid-inducible proteins and enzymes, the o ne singled out in these studies as of potential mechanistic significan ce in the protective effect of thyroid in ARF is ornithine decarboxyla se (ODC). This enzyme catalyzes the entry step in the biosynthesis of polyamines, which possess several potential roles in fostering renal r epair and recovery. Ischemic ARF was induced in rats by renal arterial clamp and functional assessment was made by inulin clearance 24 h aft er injury. Both T-4 (10 mu g/100 g) and T-3 (1 and 10 mu g/100 g) resu lted in significant improvement in inulin clearance when compared to i schemia alone, while reverse T-3 was without effect. The activity of O DC was reduced 70% at 24 h in the kidney cortex but T-3 restored the l evel to near control. Pretreatment of rats with difluromerhylornithine (DFMO), an irreversible inhibitor of ODC, resulted in nearly complete inhibition of this enzyme in the cortex and medulla, and blocked the increase in activity induced by T-3. From the functional standpoint, D MFO did not worsen the severity of ischemic ARF but completely blocked the protective effect of T-3. These data strongly suggest roles for O DC stimulation and, presumably, the consequent augmentation of polyami ne biosynthesis, in the mechanism by which thyroid hormone enhances re covery from ARF.