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Induction and Targeting of the Glutamine Transporter SN1 to the Basolateral Membranes of Cortical Kidney Tubule Cells during Chronic Metabolic Acidosis Suggest a Role in pH Regulation

Tom Tallak Solbu^*, Jean-Luc Boulland^*, Wasim Zahid^*, May Kristin Lyamouri Bredahl^*, Mahmood Amiry-Moghaddam^*, Jon Storm-Mathisen^*, Bjørg Åse Roberg and Farrukh A. Chaudhry^*

^* Department of Anatomy and Centre for Molecular Biology and Neuroscience, Neurochemical Section, Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

Address correspondence to: Dr. Farrukh A. Chaudhry, Institute of Basic Medical Sciences and Centre for Molecular Biology and Neuroscience, P.O. Box 1105 Blindern, University of Oslo, N-0317 Oslo, Norway. Phone: +47-22851255; Fax: +47-22851278; E-mail: f.a.chaudhry{at}basalmed.uio.no

Received for publication June 2, 2004. Accepted for publication December 29, 2004.

During chronic metabolic acidosis (CMA), the plasma levels of glutamine are increased and so is glutamine metabolism in the kidney tubule cells. Degradation of glutamine results in the formation of ammonium (NH₄⁺) and bicarbonate (HCO₃^–) ions, which are excreted in the pre-urine and transported to the peritubular blood, respectively. This process contributes to counteract acidosis and to restore normal pH, but the molecular mechanism, the localization of the proteins involved and the regulation of glutamine transport into the renal tubular cells, remains unknown. SN1, a Na⁺- and H⁺-dependent glutamine transporter has previously been identified molecularly, and its mRNA has been detected in tubule cells in the medulla of the kidney. Now shown is the selective targeting of the protein to the basolateral membranes of the renal tubule cells of the S3 segment throughout development of the normal rat kidney. During CMA, SN1 expression increases five- to six-fold and appears also in cortical tubule cells in parallel with the increased expression and activity of phosphate-activated glutaminase, a mitochondrial enzyme involved in ammoniagenesis. However, SN1 remains sorted to the basolateral membranes. The unique ability of SN1 to change transport direction according to physiologic changes in transmembrane gradients of [glutamine] and pH and its sorting to the basolateral membranes and the presence of a putative pH responsive element in the 3' untranslated region (UTR) of the gene (supported here by the demonstration in CMA kidney of a protein that binds SN1 mRNA) are conducive to the function of this transporter in pH regulation.

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