Abstract
Klotho is an aging-suppression protein predominantly expressed in kidney, parathyroid glands, and choroids plexus of the brain. The extracellular domain of Klotho, a type-1 membrane protein, is secreted into urine and blood and may function as an endocrine or paracrine hormone. The functional role of Klotho in the kidney remains largely unknown. Recent studies reported that treatment by the extracellular domain of Klotho (KLe) increases cell-surface abundance of transient receptor potential vanilloid type isoform 5, an epithelial Ca2+ channel critical for Ca2+ reabsorption in the kidney. Whether Klotho regulates surface expression of other channels in the kidney is not known. Here, we report that KLe treatment increases the cell-membrane abundance of the renal K+ channel renal outer medullary potassium channel 1 (ROMK1) by removing terminal sialic acids from N-glycan of the channel. Removal of sialic acids exposes underlying disaccharide galactose-N-acetylglucosamine, a ligand for a ubiquitous galactoside-binding lectin galectin-1. Binding to galectin-1 at the extracellular surface prevents clathrin-mediated endocytosis of ROMK1 and leads to accumulation of functional channel on the plasma membrane. Intravenous administration of KLe increases the level of Klotho in urine and increases urinary excretion of K+. These results suggest that Klotho may have a broader function in the regulation of ion transport in the kidney.
Footnotes
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This work was supported by grants from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK20543, DK59530, DK79328]; the National Institutes of Health National Institute on Aging [Grants AG19712, AG19712]; the American Heart Association [Grant 0440019N]; the Eisai Research Fund; the Ellison Medical Foundation; and the Ted Nash Long Life Foundation. The Consortium for Functional Glycomics was supported by the National Institutes of Health National Institute on Aging [Grant GM62116].
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ABBREVIATIONS: FGF, fibroblast growth factor; KLe, extracellular domain of Klotho; KL1 and KL2, repeat 1 and 2 of the extracellular domain of Klotho; ROMK1, renal outer medullary potassium channel 1; TRPV5, transient receptor potential vanilloid type isoform 5; HEK, human embryonic kidney; CHO, Chinese hamster ovary; GFP, green fluorescent protein; ST6, α2,6-sialyltransferases; ST6Gal-1, galactosyl-α2,6-sialyltransferase isoform-1; ST3Gal-1, galactosyl-α2,3-sialyltransferase isoform-1; CHC, clathrin heavy chain; Cav-1, caveolin-1; DANA, 2-deoxy-2,3-dehyro-N-acetylneuraminic acid; GnT-V, N-acetylglucosaminyltransferase V; LacNAc, N-acetyllactosamine; GlcNAc, N-acetylglucosamine; SNA, Sambucus nigra agglutinin; siRNA, small interference RNA; PBS, phosphate-buffered saline; DN, dominant-negative; DN DII, dominant-negative dynamin II; WT DII, wild-type dynamin II.
- Accepted April 6, 2009.
- Received February 20, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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