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1 Institute of Physiology, University of Zurich, Zurich, Switzerland; Institute of Anatomy, University of Zurich, Zurich, Switzerland
2 Institute of Physiology, University of Zurich, Zurich, Switzerland
3 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
4 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
5 Institute of Anatomy, University of Zurich, Zurich, Switzerland
* To whom correspondence should be addressed. E-mail: Wagnerca{at}access.unizh.ch.
The Na+/phosphate cotransporter NaPi-IIa (SLC34A1) is the major transporter mediating the reabsorption of inorganic phosphate (Pi) in the proximal tubule. The expression and activity of NaPi-IIa is regulated by several factors including parathyroid hormone, dopamine, metabolic acidosis, or dietary Pi intake. Dopamine induces both natriuresis and phosphaturia in vivo and its actions on several Na+-transporting systems such as NHE3 and Na+/K+-ATPase have been investigated in detail. Here we examined its acute effects on NaPi-IIa expression and localization using freshly isolated mouse kidney slices, perfused proximal tubules, and cultured renal epithelial cells. Incubation of isolated kidney slices with the selective D1-like receptor agonists fenoldopam (10 µM) or SKF38393 (10 µM) for 1 h. induced NaPi-IIa internalization and reduced the expression of NaPi-IIa in the brush border membrane. In contrast, the D2-like selective agonist quinpirole (1 µM) had no effect. The D1 and D2 agonists did not affect the renal Na+/sulphate cotransporter NaSi in the brush border membrane of the proximal tubule. Studies with isolated perfused proximal tubules demonstrated that activation of luminal but not basolateral D1-like receptors caused NaPi-IIa internalization. In kidney slices inhibition of protein kinase C (1 µM chelerythrine) or ERK1/2 (20 µM PD098089) pathways did not prevent the fenoldopam induced internalization. However, inhibition with the protein kinase A blocker H-89 (10 µM) abolished the effect of fenoldopam. Immunoblot demonstrated a reduction of NaPi-IIa protein in the brush border membranes from kidney slices treated with fenoldopam. Incubation of OK cells transfected with NaPi-IIa/GFP chimera shifted the fluorescence from the apical membrane to an intracellular pool. In summary, dopamine induces internalization of the Na+/phosphate cotransporter NaPi-IIa by activation of luminal D1-like receptors. This effect is mediated by protein kinase A.
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