RGD Reference Report - Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus. - Rat Genome Database

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Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus.

Authors: Mamenko, Mykola  Dhande, Isha  Tomilin, Viktor  Zaika, Oleg  Boukelmoune, Nabila  Zhu, Yaming  Gonzalez-Garay, Manuel L  Pochynyuk, Oleh  Doris, Peter A 
Citation: Mamenko M, etal., J Am Soc Nephrol. 2016 Jul;27(7):2035-48. doi: 10.1681/ASN.2014121200. Epub 2015 Nov 16.
RGD ID: 150429659
Pubmed: PMID:26574044   (View Abstract at PubMed)
PMCID: PMC4926963   (View Article at PubMed Central)
DOI: DOI:10.1681/ASN.2014121200   (Journal Full-text)

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.



Disease Annotations    

Phenotype Annotations    
Objects Annotated

Genes (Rattus norvegicus)
Stim1  (stromal interaction molecule 1)

Genes (Mus musculus)
Stim1  (stromal interaction molecule 1)

Genes (Homo sapiens)
STIM1  (stromal interaction molecule 1)

Strains
SHRSP/A3  (NA)


Additional Information