Journal article
Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain
The FASEB journal, Vol.33(1), pp.1051-1061
01/01/2019
DOI: 10.1096/fj.201801023R
PMID: 30148674
Abstract
The Kelch-like 3 (KLHL3) mutations contributed to the most common causative genes in patients with pseudohypoaldosteronism type II (PHAII); however, the molecular mechanisms of PHAII-causing mutations in BTB domain of KLHL3in vivo have not been investigated. We generated and analyzed Klhl3 knock-in (KI) mice carrying a missense M131V mutation in the BTB domain (corresponding to human KLHL3 M78V mutation). Klhl3(M131V/+) KI mice exhibited typical PHAII phenotype with an exaggerated diuretic response to hydrochlorothiazide. Their kidney tissues showed an unchanged KLHL3, decreased cullin 3 (Cul3), and increased with-no-lysine kinases (WNKs) WNK1 and WNK4 along with an enhanced downstream ste20-related proline/alanine-rich kinase/oxidative stress response kinase 1-N(K)CC phosphorylation. Their Cul3 protein in the cytosol of distal convoluted tubule cells was also significantly attenuated on immunogold-labeling electron microscopy. In microdissected renal tubules, Klhl3(M131V/+) KI mice expressed high levels of Wnk4 mRNA in the distal nephron. In vitro coimmunoprecipitation showed the KLHL3 BTB domain mutation retained intact interaction with WNKs but reduced binding to Cul3, thus leading to the increased abundance of total WNKs. In summary, Klhl3(M131V/+) KI mice feature typical PHAII with a simultaneous increase of WNK1 and WNK4 through the impaired KLHL3 BTB domain binding to Cul3.Lin, C.-M., Cheng, C.-J., Yang, S.-S., Tseng, M.-H., Yen, M.-T., Sung, C.-C., Lin, S.-H. Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain.
Details
- Title: Subtitle
- Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain
- Creators
- Chien-Ming Lin - National Defense Medical CenterChih-Jen Cheng - Tri-Service General HospitalSung-Sen Yang - National Defense Medical CenterMin-Hua Tseng - Chang Gung Memorial HospitalMing-Tso Yen - National Defense Medical CenterChih-Chien Sung - National Defense Medical CenterShih-Hua Lin - National Defense Medical Center
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.33(1), pp.1051-1061
- DOI
- 10.1096/fj.201801023R
- PMID
- 30148674
- NLM abbreviation
- FASEB J
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Publisher
- Federation Amer Soc Exp Biol
- Number of pages
- 11
- Grant note
- Teh-Tzer Study Group for Human Medical Research Foundation 103-2314-B-016-010-MY3; 104-2314-B-016-023-MY3; 107-2314-B-016-064-MY3 / Ministry of Science and Technology (MOST); Ministry of Science and Technology, China C105-110; C106-091; C106-007-S03; C107-015 / Research Fund of Tri-Service General Hospital (TSGH)
- Language
- English
- Date published
- 01/01/2019
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984383914002771
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