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Reduced intestinal and renal amino acid transport in PDK1 hypomorphic mice

Rexhep Rexhepaj^*,1, Florian Grahammer^*,1, Harald Völkl, Christine Remy, Carsten A. Wagner, Diana Sandulache^*, Ferruh Artunc^*, Guido Henke^*, Srinivas Nammi^*, Giovambattista Capasso, Dario R. Alessi^|| and Florian Lang^*,1,2

^* Department of Physiology I, University of Tübingen, Germany;

Department of Physiology, Medical University, Innsbruck, Austria;

Institute of Physiology and Center of Integrative Human Physiology, University of Zürich, Switzerland;

Chair of Nephrology, Second University of Napoli, Italy; and

^|| Department of Biochemistry, University of Dundee, UK

²Correspondence: Department of Physiology, University of Tübingen Gmelinstr. 5, D-72076 Tübingen, Germany. E-mail: florian.lang{at}uni-tuebingen.de

The phosphoinositide-dependent kinase PDK1 activates the serum- and glucocorticoid-inducible kinase isoforms SGK1, SGK2, and SGK3 and protein kinase B, which in turn are known to up-regulate a variety of sodium-coupled transporters. The present study was performed to explore the role of PDK1 in amino acid transport. As mice completely lacking functional PDK1 are not viable, mice expressing 10–25% of PDK1 (pdk1^hm) were compared with their wild-type (WT) littermates (pdk1^wt). Body weight was significantly less in pdk1^hm than in pdk1^wtmice. Despite lower body weight of pdk1^hmmice, food and water intake were similar in pdk1^hm and pdk1^wtmice. According to Ussing chamber experiments, electrogenic transport of phenylalanine, cysteine, glutamine, proline, leucine, and tryptophan was significantly smaller in jejunum of pdk1^hmmice than in pdk1^wt mice. Similarly, electrogenic transport of phenylalanine, glutamine, and proline was significantly decreased in isolated perfused proximal tubules of pdk1^hmmice. The urinary excretion of proline, valine, guanidinoacetate, methionine, phenylalanine, citrulline, glutamine/glutamate, and tryptophan was significantly larger in pdk1^hm than in pdk1^wtmice. According to immunoblotting of brush border membrane proteins prepared from kidney, expression of the Na⁺-dependent neutral amino acid transporter B⁰AT1 (SLC6A19), the glutamate transporter EAAC1/EAAT3 (SLC1A1), and the transporter for cationic amino acids and cystine b^0,+AT (SLC7A9) was decreased but the Na⁺/proline cotransporter SIT (SLC6A20) was increased in pdk1^hm mice. In conclusion, reduction of functional PDK1 leads to impairment of intestinal absorption and renal reabsorption of amino acids. The combined intestinal and renal loss of amino acids may contribute to the growth defect of PDK1-deficient mice.—Rexhepaj, R., Grahammer, F., Völkl, H., Remy, C., Wagner, C. A., Sandulache, D., Artunc, F., Henke, G., Nammi, S., Capasso, G., Alessi, D. R., Lang, F. Reduced intestinal and renal amino acid transport in PDK1 hypomorphic mice.

Key Words: aminoaciduria • PI3 kinase • growth factors • SGK • PKB

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