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CaSR signaling down‐regulates AQP2 expression via a novel microRNA pathway in pendrin and NaCl cotransporter knockout mice
Author(s) -
Ranieri Marianna,
Zahedi Kamyar,
Tamma Grazia,
Centrone Mariangela,
Di Mise Annarita,
Soleimani Manoocher,
Valenti Giovanna
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700412rr
Subject(s) - pendrin , knockout mouse , cotransporter , aquaporin 2 , microrna , microbiology and biotechnology , signal transduction , biology , chemistry , medicine , receptor , transporter , gene , genetics , water channel , sodium , mechanical engineering , engineering , inlet , organic chemistry
High concentrations of urinary calcium counteract vasopressin action via the activation of the calcium‐sensing receptor (CaSR) that is expressed in the luminal membrane of collecting duct cells, which impairs the trafficking of aquaporin‐2 (AQP2). Pendrin/NaCl cotransporter double‐knockout (dKO) mice display significant calcium wasting and develop severe volume depletion, despite increased circulating vasopressin levels. We hypothesized that the CaSR‐mediated impairment of AQP2 expression/trafficking underlies vasopressin resistance in dKO mice. Compared with wild‐type mice, in renal inner medulla, dKO mice had reduced total AQP2 sensitive to proteasome inhibitors, higher levels of AQP2‐pS261, ubiquitinated AQP2, and p38‐MAPK, an enzyme that is activated by CaSR signaling and known to phosphorylate AQP2 at Ser261. CaSR inhibition with the calcilytic NPS2143 reversed these effects, which indicates that CaSR mediates the up‐regulation of AQP2‐pS261, ubiquitination, and degradation. Of note, dKO mice demonstrated significantly higher AQP2‐targeting miRNA‐137 that was reduced upon CaSR inhibition, supporting a critical role for CaSR in the down‐regulation of AQP2 expression. Our data indicate that CaSR signaling reduces AQP2 abundance both via AQP2‐targeting miRNA‐137 and the p38‐MAPK/AQP2‐pS261/ubiquitination/proteasomal axis. These effects may contribute to the reduced renal concentrating ability that has been observed in dKO mice and underscore a physiologic mechanism of the CaSR‐dependent regulation of AQP2 abundance via a novel microRNA pathway.— Ranieri, M., Zahedi, K., Tamma, G., Centrone, M., Di Mise, A., Soleimani, M., Valenti, G. CaSR signaling down‐regulates AQP2 expression via a novel microRNA pathway in pendrin and NaCl cotransporter knockout mice. FASEB J. 32, 2148–2159 (2018). www.fasebj.org