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-3) increases NHE3 activity. T-3 stimulated NKE3 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. T-3 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 Ts when expressed in OK cells. When heterologously expressed rat NKE3 transcript levels were clamped constant with a constitutive promoter in OK cells, T-3 has no effect on rat NHE3 protein abundance, suggesting the absence of regular ion of NHE3 protein stability or translation. These studies demonstrate that T-3 stimulates NHE3 activity by activating NKE3 gene transcription and increasing NHE3 transcript and protein abundance.