A critical period for the role of thyroid hormone in development of renal alpha-adrenergic receptors.

Adrenergic input influences renal cell replication/differentiation and the development of excretory function. Kidney cells make adrenoceptors before the arrival of the majority of nerve terminals, and the current study examines whether thyroid hormone plays a role in receptor development. Propylthiouracil (PTU) was given to pregnant and neonatal rats from gestational d 17 through postnatal d 5, a treatment that obtunds thyroid hormone levels throughout the first 2-3 wk postpartum. The PTU group showed significant deficits in the number of alpha1-receptors, and values resolved to normal in parallel with hormone level recovery. The effects were not secondary to alterations in cell differentiation or growth. as the period of receptor abnormalities did not correspond to that of growth inhibition. Similarly, the effects were selective for the alpha1-receptor, as no comparable effects were seen for total membrane protein or for alpha2-receptors. The role of thyroid hormone in alpha1-receptor ontogeny involved a critical developmental window; later in development neither treatment with PTU nor with large doses of thyroid hormone had any impact on alpha1-receptors. Studies of mRNAs encoding the alpha1-receptor subtypes indicated that hypothyroidism targets the alpha1a-subtype, which has been implicated in the transduction of neurotrophic signals; alpha1a-receptor mRNA also showed the largest proportional developmental increase compared with those encoding other alpha1-subtypes. Accordingly, thyroid hormone is likely to set the stage for the subsequent trophic control of renal development by neural input, and hypothyroidism during this critical window can be expected to result in abnormal renal functional development and increased perinatal risk.

Duke Scholars

Author Frederic J. Seidler Pharmacology & Cancer Biology

Author Theodore Alan Slotkin Pharmacology & Cancer Biology