Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency
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 sy...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-10-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.151039 |
| _version_ | 1811226936341430272 |
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| author | Meng-Hsuan Lin Jen-Chi Chen Xuejiao Tian Chia-Ming Lee I-Shing Yu Yi-Fen Lo Shinichi Uchida Chou-Long Huang Bi-Chang Chen Chih-Jen Cheng |
| author_facet | Meng-Hsuan Lin Jen-Chi Chen Xuejiao Tian Chia-Ming Lee I-Shing Yu Yi-Fen Lo Shinichi Uchida Chou-Long Huang Bi-Chang Chen Chih-Jen Cheng |
| author_sort | Meng-Hsuan Lin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:33:08Z |
| format | Article |
| id | doaj.art-1179e61209f04855a4e431e99348e335 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T09:33:08Z |
| publishDate | 2021-10-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-1179e61209f04855a4e431e99348e3352022-12-22T03:38:17ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-10-01620Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiencyMeng-Hsuan LinJen-Chi ChenXuejiao TianChia-Ming LeeI-Shing YuYi-Fen LoShinichi UchidaChou-Long HuangBi-Chang ChenChih-Jen ChengThe 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.https://doi.org/10.1172/jci.insight.151039Nephrology |
| spellingShingle | Meng-Hsuan Lin Jen-Chi Chen Xuejiao Tian Chia-Ming Lee I-Shing Yu Yi-Fen Lo Shinichi Uchida Chou-Long Huang Bi-Chang Chen Chih-Jen Cheng Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency JCI Insight Nephrology |
| title | Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency |
| title_full | Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency |
| title_fullStr | Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency |
| title_full_unstemmed | Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency |
| title_short | Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency |
| title_sort | impairment in renal medulla development underlies salt wasting in clc k2 channel deficiency |
| topic | Nephrology |
| url | https://doi.org/10.1172/jci.insight.151039 |
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