Hypothyroidism increases osmotic water permeability (Pf) in the developing renal brush border membrane

The osmotic water permeability (P_f) of the rabbit proximal tubule brush border membrane vesicles (BBMV) increases during maturation and is mediated by an increase in aquaporin-1 (AQP1) protein expression. Serum thyroid hormone levels increase after birth and have been shown to play a role in the maturation of other renal transport functions. We examined the hypothesis that thyroid hormone plays a role in the maturational increase in osmotic water permeability. Hypothyroidism was induced by addition of 0.1% propylthiouracil (PTU) to the drinking water of pregnant rabbits (starting 9 d before delivery) and was continued until the rabbits were studied as adults (9-11 wk). Some animals received thyroid hormone replacement by daily injection with triiodothyronine (T₃; 10 μg/100 g body weight) for three days before study. P_f was found to be higher in BBMV from hypothyroid (82.7 ± 5.5 μm/s) than from euthyroid (60.6 ± 4.0 μm/s) and T₃-replacement rabbits (69.0 ± 5.0 μm/s) (p < 0.05). The activation energy (E_a; in kcal/deg·mol) of P_f was not different among the three experimental groups (euthyroid 5.6 ± 0.9, hypothyroid 4.9 ± 0.8, T₃-replacement 5.0 ± 1.0; p = NS), nor was the percentage mercury inhibition of P_f (euthyroid 66.5 ± 5.3, hypothyroid 74.2 ± 3.2 and T₃-replacement 73.1 ± 4.3; p = NS). AQP1 expression, measured by immunoblotting, was highest in BBMV from hypothyroid rabbits (p < 0.05). Membrane fluidity, measured as steady-state generalized polarization (GP) of Laurdan, which is inversely related to membrane fluidity, was significantly different between the three groups (GP: euthyroid 0.307 ± 0.004, hypothyroid 0.271 ± 0.004 and T₃-replacement 0.287 ± 0.003; for all p < 0.05). These data demonstrate that the maturational increase in thyroid hormone levels is not responsible for the maturational increase in water transport. Surprisingly, congenital hypothyroidism in rabbits is associated with an increased P_f when rabbits are studied as adults. The higher P_f in hypothyroid adult rabbits is due to a higher expression of AQP1 protein as well as a greater membrane fluidity than in euthyroid rabbits.