Thyroid hormone induction of ornithine decarboxylase in ischemic acute renal failure.
Thyroid hormone is an important interventional agent shown to be beneficial in a variety of models of acute renal failure (ARF). While its usefulness is clear, its mechanism of action remains unknown. Although there are a multitude of thyroid-inducible proteins and enzymes, the one singled out in these studies as of potential mechanistic significance in the protective effect of thyroid in ARF is ornithine decarboxylase (ODC). This enzyme catalyzes the entry step in the biosynthesis of polyamines, which possess several potential roles in fostering renal repair and recovery. Ischemic ARF was induced in rats by renal arterial clamp and functional assessment was made by inulin clearance 24 h after injury. Both T4 (10 micrograms/100 g) and T3 (1 and 10 micrograms/100 g) resulted in significant improvement in inulin clearance when compared to ischemia alone, while reverse T3 was without effect. The activity of ODC was reduced 70% at 24 h in the kidney cortex but T3 restored the level to near control. Pretreatment of rats with difluoromethylornithine (DFMO), and 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 T3. From the functional standpoint, DMFO did not worsen the severity of ischemic ARF but completely blocked the protective effect of T3. These data strongly suggest roles for ODC stimulation and, presumably, the consequent augmentation of polyamine biosynthesis, in the mechanism by which thyroid hormone enhances recovery from ARF.
Johnson
J P
JP
Department of Nephrology, Walter Reed Army Institute of Research, Washington, DC 20307.
Grillo
F G
FG
D058186:Acute Kidney Injury / Q000188:drug therapy / Q000201:enzymology*; D000818:Animals; D000518:Eflornithine / Q000494:pharmacology; D004790:Enzyme Induction; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D065108:Ornithine Decarboxylase Inhibitors; D011292:Premedication; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013963:Thyroid Hormones / Q000494:pharmacology* / Q000627:therapeutic use
D065108:Ornithine Decarboxylase Inhibitors; D013963:Thyroid Hormones; D009955:Ornithine Decarboxylase; D000254:Sodium-Potassium-Exchanging ATPase; D000518:Eflornithine