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Thyroid hormone induction of ornithine decarboxylase in ischemic acute renal failure
1Department of Nephrology, Walter Reed Army Institute of Research, Washington, DC 20307.
Abstract:
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.
Insights
Thyroid hormone aids recovery from acute renal failure (ARF) by increasing ornithine decarboxylase (ODC) activity. Inhibiting ODC blocks this protective effect, suggesting polyamine synthesis is key to thyroid hormone
Area of Science:
- Nephrology
- Endocrinology
- Biochemistry
Background:
- Thyroid hormone has shown benefits in acute renal failure (ARF) models.
- The precise mechanism behind thyroid hormone's protective effects in ARF is not fully understood.
- Ornithine decarboxylase (ODC) is a key thyroid-inducible enzyme involved in polyamine biosynthesis.
Purpose of the Study:
- To investigate the role of ornithine decarboxylase (ODC) in the protective mechanism of thyroid hormone during acute renal failure (ARF).
- To determine if ODC stimulation and subsequent polyamine biosynthesis are essential for thyroid hormone's beneficial effects on kidney function recovery.
Main Methods:
- Ischemic ARF was induced in rats using a renal arterial clamp.
- Functional recovery was assessed by measuring inulin clearance 24 hours post-injury.
- The effects of T3, T4, reverse T3, and the ODC inhibitor difluoromethylornithine (DFMO) on kidney function and ODC activity were evaluated.
Main Results:
- T3 and T4 administration significantly improved inulin clearance in ischemic ARF rats, while reverse T3 had no effect.
- Thyroid hormone treatment restored the reduced ODC activity in the injured kidney cortex.
- Difluoromethylornithine (DFMO) blocked the T3-induced increase in ODC activity and completely abolished the protective effect of T3 on kidney function.
Conclusions:
- Thyroid hormone enhances recovery from ischemic acute renal failure (ARF) in rats.
- The enzyme ornithine decarboxylase (ODC) plays a crucial role in mediating the protective effects of thyroid hormone.
- Stimulation of polyamine biosynthesis via ODC is a likely mechanism through which thyroid hormone promotes renal repair and recovery.