title: Activation of protein kinase C-α and Src kinase increases urea transporter A1 α-2, 6 sialylation.
abstract: The urea transporter A1 (UT-A1) is a glycosylated protein with two glycoforms: 117 and 97 kD. In diabetes, the increased abundance of the heavily glycosylated 117-kD UT-A1 corresponds to an increase of kidney tubule urea permeability. We previously reported that diabetes not only causes an increase of UT-A1 protein abundance but also, results in UT-A1 glycan changes, including an increase of sialic acid content. Because activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway is elevated in diabetes and PKC-α regulates UT-A1 urea transport activity, we explored the role of PKC in UT-A1 glycan sialylation. We found that activation of PKC specifically promotes UT-A1 glycan sialylation in both UT-A1-MDCK cells and rat kidney inner medullary collecting duct suspensions, and inhibition of PKC activity blocks high glucose-induced UT-A1 sialylation. Overexpression of PKC-α promoted UT-A1 sialylation and membrane surface expression. Conversely, PKC-α-deficient mice had significantly less sialylated UT-A1 compared with wild-type mice. Furthermore, the effect of PKC-α-induced UT-A1 sialylation was mainly mediated by Src kinase but not Raf-1 kinase. Functionally, increased UT-A1 sialylation corresponded with enhanced urea transport activity. Thus, our results reveal a novel mechanism by which PKC regulates UT-A1 function by increasing glycan sialylation through Src kinase pathways, which may have an important role in preventing the osmotic diuresis caused by glucosuria under diabetic conditions.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China; and Department of Physiology and.
authors.forename: Xuechen
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China; and.
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Physiology and.
authors.forename: Minguang
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Physiology and Renal Division, Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Janet D
authors.initials: JD
authors.lastname: Klein
authors.affiliation: Department of Physiology and Renal Division, Department of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Sands
authors.affiliation: Department of Physiology and Renal Division, Department of Medicine, Emory University, Atlanta, Georgia gchen3@emory.edu baoxue@bjmu.edu.
authors.forename: Guangping
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D004285:Dogs; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D011134:Polysaccharides / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012794:Sialic Acids / Q000378:metabolism*; D014982:Xenopus laevis; D019061:src-Family Kinases / Q000378:metabolism*; D000096982:Urea Transporters
chemical_list: D026901:Membrane Transport Proteins; D011134:Polysaccharides; D051571:Protein Kinase C-alpha; D019908:Proto-Oncogene Proteins c-raf; D012794:Sialic Acids; D019061:src-Family Kinases; D000096982:Urea Transporters
keywords: diabetes; renal tubular epithelial cells; urea; vasopressin