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dc.contributor.authorLee, Aven
dc.contributor.authorSlattery, Craig
dc.contributor.authorNikolic-Paterson, David J
dc.contributor.authorHryciw, Deanne H
dc.contributor.authorWilk, Sherwin
dc.contributor.authorWilk, Elizabeth
dc.contributor.authorZhang, Yuan
dc.contributor.authorValova, Valentina A
dc.contributor.authorRobinson, Phillip J
dc.contributor.authorKelly, Darren J
dc.contributor.authorPoronnik, Philip
dc.description.abstractClC-5 is a chloride/proton exchanger that plays an obligate role in albumin uptake by the renal proximal tubule. ClC-5 forms an endocytic complex with the albumin receptor megalin/cubilin. We have identified a novel ClC-5 binding partner, cytosolic aspartyl aminopeptidase (DNPEP; EC, that catalyzes the release of N-terminal aspartate/glutamate residues. The physiological role of DNPEP remains largely unresolved. Mass spectrometric analysis of proteins binding to the glutathione-S-transferase (GST)-ClC-5 C terminus identified DNPEP as an interacting partner. Coimmunoprecipitation confirmed that DNPEP and ClC-5 also associated in cells. Further experiments using purified GST-ClC-5 and His-DNPEP proteins demonstrated that the two proteins bound directly to each other. In opossum kidney (OK) cells, confocal immunofluorescence studies revealed that DNPEP colocalized with albumin-containing endocytic vesicles. Overexpression of wild-type DNPEP increased cell-surface levels of ClC-5 and albumin uptake. Analysis of DNPEP-immunoprecipitated products from rat kidney lysate identified β-actin and tubulin, suggesting a role for DNPEP in cytoskeletal maintenance. A DNase I inhibition assay showed a significant decrease in the amount of G actin when DNPEP was overexpressed in OK cells, suggesting a role for DNPEP in stabilizing the cytoskeleton. DNPEP was not present in the urine of healthy rats; however, it was readily detected in the urine in rat models of mild and heavy proteinuria (diabetic nephropathy and anti-glomerular basement membrane disease, respectively). Urinary levels of DNPEP were found to correlate with the severity of proteinuria. Therefore, we have identified another key molecular component of the albumin endocytic machinery in the renal proximal tubule and describe a new role for DNPEP in stabilizing the actin cytoskeleton.
dc.publisherAmerican Physiological Society
dc.relation.ispartofjournalAmerican Journal of Physiology: Renal Physiology
dc.subject.fieldofresearchMedical Physiology not elsewhere classified
dc.subject.fieldofresearchClinical Sciences
dc.subject.fieldofresearchMedical Physiology
dc.titleChloride Channel ClC-5 Binds to Aspartyl Aminopeptidase to Regulate Renal Albumin Endocytosis
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorSkelly, Deanne

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