Albumin Regulates the Na⁺/H⁺ Exchanger 3 in OKP Cells

Albumin filtered by the glomerulus is reabsorbed in the proximal tubule. We have shown previously that protein-uria stimulates the proximal tubular Na⁺/H⁺ exchanger 3 (NHE3) in rats. Activation of NHE3 may be a pathophysiologically important factor in the development of renal salt and water retention observed in the nephrotic syndrome. For examining whether albumin is a specific inducer of proximal tubular Na⁺/H⁺ exchange and to determine the molecular mechanisms by which it regulates Na+/H+ exchange, the effect of albumin on NHE3 in opossum kidney cells was studied. Albumin activated Na⁺/H⁺ exchange in a time- and dose-dependent manner up to 100% in 48 h. In the early phase of stimulation (2 to 12 h), NHE3 activity was increased without changes in NHE3 protein and mRNA. At 24 h, increased NHE3 activity was accompanied by increase in cell surface NHE3 protein. The increase in surface NHE3 was associated with increased bidirectional trafficking of NHE3 protein between intracellular compartments and the cell surface. At 48 h, total cell NHE3 protein abundance and mRNA were increased as well. Whereas NHE3 translation was increased, NHE3 protein half-life remained unchanged. The effects of albumin on NHE3 protein abundance were modified by hydrocortisone in a complicated pattern. These results indicate that albumin directly regulates proximal tubular NHE3 at multiple levels.