Thyroid hormone stimulates the renal Na/H exchanger NHE3 by transcriptional activation

Thyroid hormone stimulates renal proximal tubule NaCl and NaHCO₃ absorption in part by activating the apical membrane Na/H exchanger NHE3. We used a renal epithelial cell line, the opossum kidney (OK) cell, to define the mechanism by which 3,5,3'-triiodothyronine (T(a)) increases NHE3 activity. T₃ stimulated NHE3 activity, an effect that was blocked by inhibition of cellular transcription or translation. The increase in activity was associated with increases in steady-state cell surface and total cellular NHE3 protein and NHE3 transcript abundance. T₃ stimulated transcription of the NHE3 gene and had no effect on NHE3 transcript stability. The transcriptional activity of the 5'-flanking region of the rat NHE3 gene was stimulated by T₃ when expressed in OK cells. When heterologously expressed rat NHE3 transcript levels were clamped constant with a constitutive promoter in OK cells, T₃ has no effect on rat NHE3 protein abundance, suggesting the absence of regulation of NHE3 protein stability or translation. These studies demonstrate that T₃ stimulates NHE3 activity by activating NHE3 gene transcription and increasing NHE3 transcript and protein abundance.