title: Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus.
abstract: Store-operated calcium entry (SOCE) is the mechanism by which extracellular signals elicit prolonged intracellular calcium elevation to drive changes in fundamental cellular processes. Here, we investigated the role of SOCE in the regulation of renal water reabsorption, using the inbred rat strain SHR-A3 as an animal model with disrupted SOCE. We found that SHR-A3, but not SHR-B2, have a novel truncating mutation in the gene encoding stromal interaction molecule 1 (STIM1), the endoplasmic reticulum calcium (Ca(2+)) sensor that triggers SOCE. Balance studies revealed increased urine volume, hypertonic plasma, polydipsia, and impaired urinary concentrating ability accompanied by elevated circulating arginine vasopressin (AVP) levels in SHR-A3 compared with SHR-B2. Isolated, split-open collecting ducts (CD) from SHR-A3 displayed decreased basal intracellular Ca(2+) levels and a major defect in SOCE. Consequently, AVP failed to induce the sustained intracellular Ca(2+) mobilization that requires SOCE in CD cells from SHR-A3. This effect decreased the abundance of aquaporin 2 and enhanced its intracellular retention, suggesting impaired sensitivity of the CD to AVP in SHR-A3. Stim1 knockdown in cultured mpkCCDc14 cells reduced SOCE and basal intracellular Ca(2+) levels and prevented AVP-induced translocation of aquaporin 2, further suggesting the effects in SHR-A3 result from the expression of truncated STIM1. Overall, these results identify a novel mechanism of nephrogenic diabetes insipidus and uncover a role of SOCE in renal water handling.
authors.affiliation: Department of Integrative Biology and Pharmacology, and.
authors.forename: Mykola
authors.initials: M
authors.lastname: Mamenko
authors.affiliation: Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas; and.
authors.forename: Isha
authors.initials: I
authors.lastname: Dhande
authors.affiliation: Department of Integrative Biology and Pharmacology, and Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Viktor
authors.initials: V
authors.lastname: Tomilin
authors.affiliation: Department of Integrative Biology and Pharmacology, and.
authors.forename: Oleg
authors.initials: O
authors.lastname: Zaika
authors.affiliation: Department of Integrative Biology and Pharmacology, and.
authors.forename: Nabila
authors.initials: N
authors.lastname: Boukelmoune
authors.affiliation: Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas; and.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas; and.
authors.forename: Manuel L
authors.initials: ML
authors.lastname: Gonzalez-Garay
authors.affiliation: Department of Integrative Biology and Pharmacology, and peter.a.doris@uth.tmc.edu Oleh.M.Pochynyuk@uth.tmc.edu.
authors.forename: Oleh
authors.initials: O
authors.lastname: Pochynyuk
authors.affiliation: Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas; and peter.a.doris@uth.tmc.edu Oleh.M.Pochynyuk@uth.tmc.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Doris
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000502:physiology; D001127:Arginine Vasopressin / Q000502:physiology; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D018500:Diabetes Insipidus, Nephrogenic / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics; D000071737:Stromal Interaction Molecule 1 / Q000502:physiology
chemical_list: D051399:Aquaporin 2; D015220:Calcium Channels; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; D001127:Arginine Vasopressin
keywords: calcium; collecting ducts; diabetes insipidus; vasopressin; water transport