Activation of Protein Kinase C-α and Src Kinase Increases Urea Transporter A1 α-2, 6 Sialylation

Li, Xuechen; Yang, Baoxue; Chen, Minguang; Klein, Janet D.; Sands, Jeff M.; Chen, Guangping

doi:10.1681/asn.2014010026

Cited by 14 publications

(15 citation statements)

References 42 publications

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“…We recently reported that activation of PKC promotes UT-A1 glycan sialylation (18). Next, we examined whether activation of PKC also increases UT-A3 sialylation.…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported that glycosylation is an important post-translational modification for both kidney urea transporter UT-A1 (7, 8, 18) and UT-A3 (29). In the current study, we extended our studies on UT-A3 regulation by N-glycans modification.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of PKC stimulates UT-A1 glycan sialylation both in vivo and in vitro, and this effect is blocked by PKC inhibition (18). Similarly, in this study we found that activation of PKC by PDBu increased UT-A3 sialylation.…”

Section: Discussionmentioning

confidence: 99%

“…Western blotting was performed as described previously (18). Blots were probed with primary antibody, followed by anti-mouse or anti-rabbit horseradish peroxidase-conjugated secondary antibodies (GE Healthcare) and developed by ECL (GE Healthcare).…”

Section: Methodsmentioning

confidence: 99%

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Modulation of kidney urea transporter UT-A3 activity by alpha2,6-sialylation

Qian

Sands

Song

et al. 2016

Pflugers Arch - Eur J Physiol

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Two urea transporters, UT-A1 and UT-A3, are expressed in the kidney terminal inner medullary collecting duct (IMCD) and are important for the production of concentrated urine. UT-A1, as the largest isoform of all UT-A urea transporters, has gained much attention and been extensively studied; however the role and the regulation of UT-A3 are less explored. In this study, we investigated UT-A3 regulation by glycosylation modification. A site-directed mutagenesis verified a single glycosylation site in UT-A3 at Asn279. Loss of the glycosylation reduced forskolin-stimulated UT-A3 cell membrane expression and urea transport activity. UT-A3 has two glycosylation forms, 45 kDa and 65 kDa. Using sugar specific-binding lectins, the UT-A3 glycosylation profile was examined. The 45 kDa form was pulled down by lectin Con A and GNL, indicating an immature glycan with a high amount of mannose (Man); whereas the 65 kDa form is a mature glycan composed of acetylglucosamine (GlcNAc), poly-N-acetyllactosame (poly-LacNAc) that was pulled down by WGA and tomato lectin, respectively. Interestingly, the mature form of UT-A3 glycan contains significant amounts of sialic acid. We explored the enzymes responsible for directing UT-A3 sialylation. Sialyltransferase ST6GalI, but not ST3GalIV, catabolizes UT-A3 α2, 6-sialylation. Activation of PKC by PDB treatment promoted UT-A3 glycan sialylation and membrane surface expression. PKC inhibitor chelerythrine blocks ST6GalI-induced UT-A3 sialylation. Increased sialylation by ST6GalI increased UT-A3 protein stability and urea transport activity. Collectively, our study reveals a novel mechanism of UT-A3 regulation by ST6GalI-mediated sialylation modification that may play an important in kidney urea reabsorption and the urinary concentrating mechanism.

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“…We recently reported that activation of PKC promotes UT-A1 glycan sialylation (18). Next, we examined whether activation of PKC also increases UT-A3 sialylation.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Modulation of kidney urea transporter UT-A3 activity by alpha2,6-sialylation

Qian

Sands

Song

et al. 2016

Pflugers Arch - Eur J Physiol

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“…Over-expression or activation of PKCα increased UT-A1 sialylation and increased UT-A1 accumulation in the apical plasma membrane (26). UT-A1 sialylation is reduced in PKCα knock-out mice.…”

Section: Ut-amentioning

confidence: 99%

Urea transport and clinical potential of urearetics

Klein

Sands

2016

Current Opinion in Nephrology and Hypertension

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Purpose of review Urea is transported by urea transporter proteins in kidney, erythrocytes, and other tissues. Mice in which different urea transporters have been knocked-out have urine concentrating defects, which has led to the development and testing of UT-A and UT-B inhibitors as urearetics. This review summarizes the knowledge gained during the past year on urea transporter regulation and investigations into the clinical potential of urearetics. Recent findings UT-A1 undergoes several post-translational modifications that increase its function by increasing UT-A1 accumulation in the apical plasma membrane. UT-A1 is phosphorylated by PKA, Epac, PKCα, and AMPK, all at different serine residues. UT-A1 is also regulated by 14-3-3, which contributes to UT-A1 removal from the membrane. UT-A1 is glycosylated with various glycan moieties in animal models of diabetes mellitus. Transgenic expression of UT-A1 into UT-A1/UT-A3 knock-out mice restores urine concentrating ability. UT-B is present in descending vasa recta and urinary bladder, and is linked to bladder cancer. Inhibitors of UT-A and UT-B have been developed that result in diuresis with fewer abnormalities in serum electrolytes than conventional diuretics. Summary Urea transporters play critical roles in the urine concentrating mechanism. Urea transport inhibitors are a promising new class of diuretic agents.

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Tea Drinking Alleviates Diabetic Symptoms via Upregulating Renal Water Reabsorption Proteins and Downregulating Renal Gluconeogenic Enzymes in db/db Mice

Zhao

Wang

et al. 2020

Molecular Nutrition Food Res

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Scope: Tea, made from the plant Camellia sinensis, is known to have anti‐diabetes effects and different mechanisms of action are proposed. Kidney is a vital organ in managing water reabsorption and glucose metabolism, and is greatly influenced by diabetes. The present study investigates the effects of tea administration on water reabsorption and gluconeogenesis in the kidney of diabetic mice. Methods and results: Db/db mice are given tea infusion as drinking fluid when they begin to exhibit hyperglycemia. It is found that green tea or black tea infusion potently elevates renal proteins vital for water reabsorption, including protein kinase C‐α, aquaporin 2, and urea transporter‐A1, as well as increases trafficking of these proteins to apical plasma membrane where they exert water reabsorption function. The treatment also downregulates renal gluconeogenic enzymes, including glucose‐6‐phosphatase‐α and phosphoenolpyruvate carboxykinase. Associated with these biochemical changes are the rectified polyuria, polydipsia, polyphagia, and hyperglycemia, all symptoms of diabetes. Conclusions: For the first time, the present study demonstrates that tea has robust effects in enhancing kidney water reabsorption proteins and downregulating gluconeogenic enzymes in db/db mice. It remains to be investigated whether such beneficial effects of tea occur in humans.

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Activation of Protein Kinase C-α and Src Kinase Increases Urea Transporter A1 α-2, 6 Sialylation

Cited by 14 publications

References 42 publications

Modulation of kidney urea transporter UT-A3 activity by alpha2,6-sialylation

Modulation of kidney urea transporter UT-A3 activity by alpha2,6-sialylation

Urea transport and clinical potential of urearetics

Tea Drinking Alleviates Diabetic Symptoms via Upregulating Renal Water Reabsorption Proteins and Downregulating Renal Gluconeogenic Enzymes in db/db Mice

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