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Renal peroxiredoxin 6 interacts with anion exchanger 1 and plays a novel role in pH homeostasis.

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Sorrell, Sara L 
Golder, Zoe J 
Johnstone, Duncan B 
Frankl, Fiona E Karet 


Peroxiredoxin 6 (PRDX6) is one of the six members of the PRDX family, which have peroxidase and antioxidant activity. PRDX6 is unique, containing only one conserved cysteine residue (C47) rather than the two found in other PRDXs. A yeast two-hybrid screen found PRDX6 to be a potential binding partner of the C-terminal tail of anion exchanger 1 (AE1), a Cl(-)/HCO(3)(-) exchanger basolaterally expressed in renal α-intercalated cells. PRDX6 immunostaining in human kidney was both cytoplasmic and peripheral and colocalized with AE1. Analysis of native protein showed that it was largely monomeric, whereas expressed tagged protein was more dimeric. Two methionine oxidation sites were identified. In vitro and ex vivo pull-downs and immunoprecipitation assays confirmed interaction with AE1, but mutation of the conserved cysteine resulted in loss of interaction. Prdx6 knockout mice had a baseline acidosis with a major respiratory component and greater AE1 expression than wild-type animals. After an oral acid challenge, PRDX6 expression increased in wild-type mice, with preservation of AE1. However, AE1 expression was significantly decreased in knockout animals. Kidneys from acidified mice showed widespread proximal tubular vacuolation in wild-type but not knockout animals. Knockdown of PRDX6 by siRNA in mammalian cells reduced both total and cell membrane AE1 levels. Thus, PRDX6-AE1 interaction contributes to the maintenance of AE1 during cellular stress such as during metabolic acidosis.



AE1, PRDX6, acidosis, cellular stress, distal tubule, renal pathology, Acidosis, Animals, Anion Exchange Protein 1, Erythrocyte, Homeostasis, Humans, Hydrogen-Ion Concentration, Immunohistochemistry, Immunoprecipitation, Kidney, Mice, Mice, Knockout, Peroxiredoxin VI

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Kidney Int

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Elsevier BV
Wellcome Trust (088489/Z/09/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (066438/Z/01/Z)
Wellcome Trust (079895/Z/06/B)
Human kidney sections were prepared by Suzy Haward, Addenbrooke's Human Research Tissue Bank, which is supported by the Cambridge Biomedical Research Centre. We thank Dr. Aron Fisher (Institute for Environmental Science, University of Pennsylvania) for the kind gift of Prdx6−/− mice and reagents, Carsten Wagner (Zurich) for antisera, Jane Clarke (University of Cambridge) for modified pRSET-A vector, and Kamburapola Jayawardena for mass spectrometry (CIMR). This work was funded by the Wellcome Trust (award 088489/Z/09/Z to FEKF and Strategic award 100140/Z/12/Z to the Cambridge Institute for Medical Research), and the Jack Kent Cooke Foundation (scholarship to SLS).