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1 Medicine, Duke University Medical Center, Durham, North Carolina, United States
2 CIIT Centers for Health Research, RTP, North Carolina, United States
3 Pathology, Duke University Medical Center, Durham, North Carolina, United States
4 Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung and Blood Instituted, Bethesda, Maryland, United States
5 Medicine, Duke University and Durham VA Medical Centers, Durham, United States
* To whom correspondence should be addressed. E-mail: thu.le{at}duke.edu.
Defects in renal proximal tubule transport manifest in a number of human diseases. Though variable in clinical presentation, disorders such as Hartnup disease, Dent's disease, and the Fanconi syndrome, are characterized by wasting of solutes commonly recovered by the proximal tubule. One common feature of these disorders is aminoaciduria. There are distinct classes of amino acid transporters located in the apical and basal membranes of the proximal tubules that reabsorb >95% of filtered amino acids, yet few details are known about their regulation. We present our physiologic characterization of a mouse line with targeted deletion of the gene collectrin that is highly expressed in the kidney. Collectrin-deficient mice display a reduced urinary concentrating capacity due to enhanced solute clearance resulting from profound aminoaciduria. The aminoaciduria is generalized, characterized by loss of nearly every amino acid, and results in marked crystalluria. Furthermore, in the kidney, collectrin-deficient mice have decreased plasma membrane populations of amino acid transporter subtypes B0AT1, rBAT, and B0,+AT, as well as altered cellular distribution of EAAC1. Our data suggest that collectrin is a novel mediator of renal amino acid transport and may provide further insight into the pathogenesis of a number of human disease correlates.
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