title: Treatment with 17-allylamino-17-demethoxygeldanamycin ameliorated symptoms of Bartter syndrome type IV caused by mutated Bsnd in mice.
abstract: Mutations of BSND, which encodes barttin, cause Bartter syndrome type IV. This disease is characterized by salt and fluid loss, hypokalemia, metabolic alkalosis, and sensorineural hearing impairment. Barttin is the β-subunit of the ClC-K chloride channel, which recruits it to the plasma membranes, and the ClC-K/barttin complex contributes to transepithelial chloride transport in the kidney and inner ear. The retention of mutant forms of barttin in the endoplasmic reticulum (ER) is etiologically linked to Bartter syndrome type IV. Here, we report that treatment with 17-allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, enhanced the plasma membrane expression of mutant barttins (R8L and G47R) in Madin-Darby canine kidney cells. Administration of 17-AAG to Bsnd(R8L/R8L) knock-in mice elevated the plasma membrane expression of R8L in the kidney and inner ear, thereby mitigating hypokalemia, metabolic alkalosis, and hearing loss. These results suggest that drugs that rescue ER-retained mutant barttin may be useful for treating patients with Bartter syndrome type IV.
authors.affiliation: Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nomura
authors.forename: Kazusaku
authors.initials: K
authors.lastname: Kamiya
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Ikeda
authors.forename: Naofumi
authors.initials: N
authors.lastname: Yui
authors.forename: Motoko
authors.initials: M
authors.lastname: Chiga
authors.forename: Eisei
authors.initials: E
authors.lastname: Sohara
authors.forename: Tatemitu
authors.initials: T
authors.lastname: Rai
authors.forename: Sei
authors.initials: S
authors.lastname: Sakaki
authors.forename: Shinich
authors.initials: S
authors.lastname: Uchida
mesh_terms: D000818:Animals; D001309:Auditory Threshold; D001477:Bartter Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D016227:Benzoquinones / Q000627:therapeutic use*; D018118:Chloride Channels; D004285:Dogs; D055879:Gene Knock-In Techniques; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006319:Hearing Loss, Sensorineural / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D007684:Kidney Tubules / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains
chemical_list: D016227:Benzoquinones; C486687:Bsnd protein, mouse; D018118:Chloride Channels; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; C112765:tanespimycin
keywords: 17-AAG; Bartter syndrome; Barttin; ClC-K; Sensorineural hearing impairment