Defective store-operated calcium entry causes partial nephrogenic diabetes insipidus

Mykola Mamenko, Isha Dhande, Viktor Tomilin, Oleg Zaika, Nabila Boukelmoune, Yaming Zhu, Manuel L. Gonzalez-Garay, Oleh Pochynyuk, Peter A. Doris

Research output: Contribution to journalArticle

15 Scopus citations

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 (Ca2+) 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 Ca2+ levels and a major defect in SOCE. Consequently, AVP failed to induce the sustained intracellular Ca2+ 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)2035-2048
Number of pages14
JournalJournal of the American Society of Nephrology
Volume27
Issue number7
DOIs
StatePublished - 2016
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

Fingerprint Dive into the research topics of 'Defective store-operated calcium entry causes partial nephrogenic diabetes insipidus'. Together they form a unique fingerprint.

  • Cite this

    Mamenko, M., Dhande, I., Tomilin, V., Zaika, O., Boukelmoune, N., Zhu, Y., Gonzalez-Garay, M. L., Pochynyuk, O., & Doris, P. A. (2016). Defective store-operated calcium entry causes partial nephrogenic diabetes insipidus. Journal of the American Society of Nephrology, 27(7), 2035-2048. https://doi.org/10.1681/ASN.2014121200