Journal article
Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency
JCI insight, Vol.6(20), e151039
10/22/2021
DOI: 10.1172/jci.insight.151039
PMCID: PMC8564913
PMID: 34499620
Abstract
The prevailing view is that the ClC-Ka chloride channel (mouse Clc-k1) functions in the thin ascending limb to control urine concentration, whereas the ClC-Kb channel (mouse Clc-k2) functions in the thick ascending limb (TAL) to control salt reabsorption. Mutations of ClC-Kb cause classic Bartter syndrome, characterized by renal salt wasting, with perinatal to adolescent onset. We studied the roles of Clc-k channels in perinatal mouse kidneys using constitutive or inducible kidney-specific gene ablation and 2D and advanced 3D imaging of optically cleared kidneys. We show that Clc-k1 and Clc-k2 were broadly expressed and colocalized in perinatal kidneys. Deletion of Clc-k1 and Clc-k2 revealed that both participated in NKCC2- and NCC-mediated NaCl reabsorption in neonatal kidneys. Embryonic deletion of Clc-k2 caused tubular injury and impaired renal medulla and TAL development. Inducible deletion of Clc-k2 beginning after medulla maturation produced mild salt wasting resulting from reduced NCC activity. Thus, both Clc-k1 and Clc-k2 contributed to salt reabsorption in TAL and distal convoluted tubule (DCT) in neonates, potentially explaining the less-severe phenotypes in classic Bartter syndrome. As opposed to the current understanding that salt wasting in adult patients with Bartter syndrome is due to Clc-k2 deficiency in adult TAL, our results suggest that it originates mainly from defects occurring in the medulla and TAL during development.
Details
- Title: Subtitle
- Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency
- Creators
- Meng-Hsuan Lin - National Defense Medical CenterJen-Chi Chen - Tri-Service General HospitalXuejiao Tian - National Tsing Hua UniversityChia-Ming Lee - Research Center for Applied Science, Academia SinicaI-Shing Yu - National Taiwan UniversityYi-Fen Lo - National Defense Medical CenterShinichi Uchida - Tokyo Medical and Dental UniversityChou-Long Huang - Roy J. and Lucille A. Carver College of MedicineBi-Chang Chen - National Tsing Hua UniversityChih-Jen Cheng - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.6(20), e151039
- DOI
- 10.1172/jci.insight.151039
- PMID
- 34499620
- PMCID
- PMC8564913
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Grant note
- MOST 107-2314-B-016-010-MY3 / ; DK111542 / ; TSGH-C106-094,TSGH-C107-095,TSGH-C108-133,TSGH-D-109124; 801GB110053 / ; MOST 106-2628-B-016-002-MY3 / ; MOST 109-2314-B-016-039-MY3 / ;
- Language
- English
- Date published
- 10/22/2021
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984359927502771
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