Loss of GCN2, an eIF2alpha kinase, does not impair urinary concentrating ability

During anti‐diuresis renal medullary cells are regularly exposed to high concentrations of urea. We reported previously that in vitro urea activates an integrated stress response via the general control non‐depressible 2 kinase (GCN2) in mIMCD3 cells; knockdown of GCN2 protected cells from high urea induced apoptosis. To determine if GCN2 activation plays a role in the urinary concentrating mechanism GCN2 null mice were infused with dDAVP, an agonist of the vasopressin type 2 receptor, for 7 days. dDAVP significantly increased urine osmolality in GCN2 null mice from 1271 ± 192 to 3758 ± 50 mosmol/kg.H 2 O. Following dDAVP infusion, aquaporin 2 (AQP2) and urea transporter A1 mRNA abundance were significantly increased in the medulla of GCN2 null mice (2.68 ± 0.12 and 1.85 ± 0.10 fold respectively). dDAVP also increased the ER stress pathway protein, activating transcription factor 4 (ATF4) mRNA abundance (2.27 ± 0.05 fold), but did not alter the expression of ATF3 and GADD153/CHOP10 in the renal medulla of GCN2 null mice. Immunohistochemistry demonstrated that dDAVP increased the expression of AQP2 in the apical membrane of principal cells in the medulla of GCN2 null mice. In conclusion, urinary concentrating ability of GCN2 null mice was not impaired and vasopressin‐regulated gene expression in renal medullary collecting duct cells was intact.