Regulation of renal outer medullary potassium channel and renal K(+) excretion by Klotho.
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 Ca(2+) channel critical for Ca(2+) 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.
Department of Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8856, USA.
Seung-Kuy
SK
Cha
Ming-Chang
MC
Hu
Hiroshi
H
Kurosu
Makoto
M
Kuro-o
Orson
O
Moe
Chou-Long
CL
Huang
D000818:Animals; D016466:CHO Cells; D002966:Clathrin / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis; D037483:Galectin 1 / Q000378:metabolism; D005966:Glucuronidase / Q000737:chemistry / Q000502:physiology*; D006031:Glycosylation; D006801:Humans; D000090265:Klotho Proteins; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000502:physiology
D002966:Clathrin; D037483:Galectin 1; C086989:KCNJ1 protein, human; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D050916:TRPV Cation Channels; C492239:TRPV5 protein, human; D005966:Glucuronidase; D000090265:Klotho Proteins; D011188:Potassium