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.

Water, Water Everywhere: A New Cause and a New Treatment for Nephrogenic Diabetes Insipidus

“…Thus, Mamenko et al 2 identified a novel genetic mutation and a novel physiologic mechanism for NDI through SOCE and STIM1 and elucidated an important role for Ca 21 signaling in the urinary concentrating mechanism. 2 The paper in JASN by de Groot et al 3 addressed a different aspect of NDI: a new therapeutic approach to lithiuminduced NDI. Lithium is used to treat manic depressive illness (reviewed in ref.…”

“…Mamenko et al 2 used whole-genome sequencing to uncover this novel mutation in the STIM1 gene. Mamenko et al 2 made this discovery using a clever approach: they crossed SHR-A3 rats with a very closely related rat, the SHR-B2. The SHR-B2 rat shares 87% of its genome with the SHR-A3 rat but lacks the STIM1 mutation present in the SHR-A3 rat.…”

“…The SHR-B2 rat shares 87% of its genome with the SHR-A3 rat but lacks the STIM1 mutation present in the SHR-A3 rat. Mamenko et al 2 found a significant relationship between the inheritance of the STIM1 SHR-A3 mutant allele and the production of dilute urine.…”

“…In addition to finding the mutation, Mamenko et al 2 performed physiologic studies to show that the STIM1 mutation present in SHR-A3 rats resulted in increased urine volume, polydipsia, hypertonic plasma, and impaired urinary concentrating ability accompanied by elevated vasopressin levels (i.e., NDI). Mamenko et al 2 used split-open collecting ducts from SHR-A3 rats and found decreased basal intracellular Ca 21 levels and a major defect in SOCE, which results in a failure of vasopressin to induce a sustained intracellular Ca 21 mobilization in SHR-A3 rat collecting ducts.…”

“…Mamenko et al 2 used split-open collecting ducts from SHR-A3 rats and found decreased basal intracellular Ca 21 levels and a major defect in SOCE, which results in a failure of vasopressin to induce a sustained intracellular Ca 21 mobilization in SHR-A3 rat collecting ducts. This led to a reduction in AQP2 protein abundance and an increase in the intracellular retention of AQP2, thereby resulting in less AQP2 in the apical plasma membrane where it is needed to reabsorb water in collecting ducts from SHR-A3 rats.…”