title: Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor.
abstract: The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent β-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112; Veterans Affairs Medical Center, Salt Lake City, UT 84108; Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China;
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Lu
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China; Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112; Veterans Affairs Medical Center, Salt Lake City, UT 84108;
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China;
authors.forename: Chuanming
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112; Veterans Affairs Medical Center, Salt Lake City, UT 84108;
authors.forename: Sunny
authors.initials: S
authors.lastname: Soodvilai
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112; Veterans Affairs Medical Center, Salt Lake City, UT 84108; Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China;
authors.forename: Kexin
authors.initials: K
authors.lastname: Peng
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China;
authors.forename: Jiahui
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112; Veterans Affairs Medical Center, Salt Lake City, UT 84108;
authors.forename: Long
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112; Veterans Affairs Medical Center, Salt Lake City, UT 84108;
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557; Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557;
authors.forename: Yumei
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33620;
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77004 jgustafsson@uh.edu Tianxin.Yang@hsc.utah.edu.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112; Veterans Affairs Medical Center, Salt Lake City, UT 84108; Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China; jgustafsson@uh.edu Tianxin.Yang@hsc.utah.edu.
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D003919:Diabetes Insipidus / Q000188:drug therapy* / Q000652:urine; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D000071518:Liver X Receptors; D008297:Male; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D009995:Osmosis; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D012995:Solubility; D013449:Sulfonamides / Q000494:pharmacology; D014556:Urine / Q000737:chemistry* / Q000502:physiology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D000093342:Prorenin Receptor; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D051399:Aquaporin 2; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D013449:Sulfonamides; D051176:beta Catenin; D000093342:Prorenin Receptor; C496025:Aqp2 protein, rat; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; C504124:FZD8 protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: aquaporin-2; frizzled-8; liver X receptor; soluble (pro)renin receptor; β-catenin