title: Liver X receptor β increases aquaporin 2 protein level via a posttranscriptional mechanism in renal collecting ducts.
abstract: Liver X receptors (LXRs) including LXRα and LXRβ are nuclear receptor transcription factors and play an important role in lipid and glucose metabolism. It has been previously reported that mice lacking LXRβ but not LXRα develop a severe urine concentrating defect, likely via a central mechanism. Here we provide evidence that LXRβ regulates water homeostasis through increasing aquaporin 2 (AQP2) protein levels in renal collecting ducts. LXRβ-/-mice exhibited a reduced response to desmopressin (dDAVP) stimulation, suggesting that the diabetes insipidus phenotype is of both central and nephrogenic origin. AQP2 protein abundance in the renal inner medulla was significantly reduced in LXRβ-/-mice but with little change in AQP2 mRNA levels. In vitro studies showed that AQP2 protein levels were elevated upon LXR agonist treatment in both primary cultured mouse inner medullary duct cells (mIMCD) and the mIMCD3 cell line with stably expressed AQP2. In addition, LXR agonists including TO901317 and GW3965 failed to induce AQP2 gene transcription but diminished its protein ubiquitination in primary cultured mIMCD cells, thereby inhibiting its degradation. Moreover, LXR activation-induced AQP2 protein expression was abolished by the protease inhibitor MG132 and the ubiquitination-deficient AQP2 (K270R). Taken together, the present study demonstrates that activation of LXRβ increases AQP2 protein levels in the renal collecting ducts via a posttranscriptional mechanism. As such, LXRβ represents a key regulator of body water homeostasis.
authors.affiliation: AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Su
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Shi-Zheng
authors.initials: SZ
authors.lastname: Huang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Xiao-Mu
authors.initials: XM
authors.lastname: Kong
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas.|Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Stockholm, Sweden; and.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Su-Juan
authors.initials: SJ
authors.lastname: Xu
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Chen
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Nan-Ping
authors.initials: NP
authors.lastname: Wang
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: You-Fei
authors.initials: YF
authors.lastname: Guan
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China wserien@163.com.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D050034:Antidiuretic Agents / Q000494:pharmacology; D051399:Aquaporin 2 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D005838:Genotype; D007671:Kidney Concentrating Ability; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism*; D000071518:Liver X Receptors / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D059748:Proteolysis; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D050034:Antidiuretic Agents; C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D000071518:Liver X Receptors; C000605211:Nr1h2 protein, mouse; D046988:Proteasome Endopeptidase Complex; D003894:Deamino Arginine Vasopressin
keywords: diabetes insipidus; gene knockout; nuclear receptor; principal cells; ubiquitination