Uromodulin Regulates Murine Aquaporin−2 Activity via Thick Ascending Limb–Collecting Duct Cross−Talk during Water Deprivation
Uromodulin, a urinary protein synthesized and secreted from the thick ascending limb (TAL) of the loop of Henle, is associated with hypertension through the activation of sodium reabsorption in the TAL. Uromodulin is a potential target for hypertension treatment via natriuresis. However, its biologi...
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/16/9410 |
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| author | Tomoaki Takata Shintaro Hamada Yukari Mae Takuji Iyama Ryohei Ogihara Misako Seno Kazuomi Nakamura Miki Takata Takaaki Sugihara Hajime Isomoto |
| author_facet | Tomoaki Takata Shintaro Hamada Yukari Mae Takuji Iyama Ryohei Ogihara Misako Seno Kazuomi Nakamura Miki Takata Takaaki Sugihara Hajime Isomoto |
| author_sort | Tomoaki Takata |
| collection | DOAJ |
| description | Uromodulin, a urinary protein synthesized and secreted from the thick ascending limb (TAL) of the loop of Henle, is associated with hypertension through the activation of sodium reabsorption in the TAL. Uromodulin is a potential target for hypertension treatment via natriuresis. However, its biological function in epithelial cells of the distal nephron segment, particularly the collecting duct, remains unknown. Herein, we examined the regulation of uromodulin production during water deprivation in vivo as well as the effect of uromodulin on the activity of the water channel aquaporin−2 (AQP2) in vitro and in vivo using transgenic mice. Water deprivation upregulated uromodulin production; immunofluorescence experiments revealed uromodulin adhesion on the apical surface of the collecting duct. Furthermore, the activation of AQP2 was attenuated in mice lacking uromodulin. Uromodulin enhanced the phosphorylation and apical trafficking of AQP2 in mouse collecting duct cells treated with the vasopressin analog dDAVP. The uromodulin-induced apical trafficking of AQP2 was attenuated via endocytosis inhibitor treatment, suggesting that uromodulin activates AQP2 through the suppression of endocytosis. This study provides novel insights into the cross−talk between TAL and the collecting duct, and indicates that the modulation of uromodulin is a promising approach for diuresis and hypertension treatment. |
| first_indexed | 2024-03-09T13:14:11Z |
| format | Article |
| id | doaj.art-0a9233aea0454568ae835a1e6d4f81f9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T13:14:11Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0a9233aea0454568ae835a1e6d4f81f92023-11-30T21:37:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012316941010.3390/ijms23169410Uromodulin Regulates Murine Aquaporin−2 Activity via Thick Ascending Limb–Collecting Duct Cross−Talk during Water DeprivationTomoaki Takata0Shintaro Hamada1Yukari Mae2Takuji Iyama3Ryohei Ogihara4Misako Seno5Kazuomi Nakamura6Miki Takata7Takaaki Sugihara8Hajime Isomoto9Division of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanDivision of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanDivision of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanDivision of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanDivision of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanAdvanced Medicine & Translational Research Center, Organization for Research Initiative and Promotion, Tottori University, Yonago 683-8504, JapanAdvanced Medicine, Innovation and Clinical Research Center, Tottori University Hospital, Yonago 683-8504, JapanDivision of Respiratory Medicine and Rheumatology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanDivision of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanDivision of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanUromodulin, a urinary protein synthesized and secreted from the thick ascending limb (TAL) of the loop of Henle, is associated with hypertension through the activation of sodium reabsorption in the TAL. Uromodulin is a potential target for hypertension treatment via natriuresis. However, its biological function in epithelial cells of the distal nephron segment, particularly the collecting duct, remains unknown. Herein, we examined the regulation of uromodulin production during water deprivation in vivo as well as the effect of uromodulin on the activity of the water channel aquaporin−2 (AQP2) in vitro and in vivo using transgenic mice. Water deprivation upregulated uromodulin production; immunofluorescence experiments revealed uromodulin adhesion on the apical surface of the collecting duct. Furthermore, the activation of AQP2 was attenuated in mice lacking uromodulin. Uromodulin enhanced the phosphorylation and apical trafficking of AQP2 in mouse collecting duct cells treated with the vasopressin analog dDAVP. The uromodulin-induced apical trafficking of AQP2 was attenuated via endocytosis inhibitor treatment, suggesting that uromodulin activates AQP2 through the suppression of endocytosis. This study provides novel insights into the cross−talk between TAL and the collecting duct, and indicates that the modulation of uromodulin is a promising approach for diuresis and hypertension treatment.https://www.mdpi.com/1422-0067/23/16/9410aquaporin−2collecting ductdiureticsendocytosishypertensionloop of Henle |
| spellingShingle | Tomoaki Takata Shintaro Hamada Yukari Mae Takuji Iyama Ryohei Ogihara Misako Seno Kazuomi Nakamura Miki Takata Takaaki Sugihara Hajime Isomoto Uromodulin Regulates Murine Aquaporin−2 Activity via Thick Ascending Limb–Collecting Duct Cross−Talk during Water Deprivation International Journal of Molecular Sciences aquaporin−2 collecting duct diuretics endocytosis hypertension loop of Henle |
| title | Uromodulin Regulates Murine Aquaporin−2 Activity via Thick Ascending Limb–Collecting Duct Cross−Talk during Water Deprivation |
| title_full | Uromodulin Regulates Murine Aquaporin−2 Activity via Thick Ascending Limb–Collecting Duct Cross−Talk during Water Deprivation |
| title_fullStr | Uromodulin Regulates Murine Aquaporin−2 Activity via Thick Ascending Limb–Collecting Duct Cross−Talk during Water Deprivation |
| title_full_unstemmed | Uromodulin Regulates Murine Aquaporin−2 Activity via Thick Ascending Limb–Collecting Duct Cross−Talk during Water Deprivation |
| title_short | Uromodulin Regulates Murine Aquaporin−2 Activity via Thick Ascending Limb–Collecting Duct Cross−Talk during Water Deprivation |
| title_sort | uromodulin regulates murine aquaporin 2 activity via thick ascending limb collecting duct cross talk during water deprivation |
| topic | aquaporin−2 collecting duct diuretics endocytosis hypertension loop of Henle |
| url | https://www.mdpi.com/1422-0067/23/16/9410 |
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