Long term dDAVP increases the expression of urea transporters and ER stress pathway genes in kidneys of mice with urinary concentrating defect.

Abstract

It is well‐know that both AQP2 and urea transporter A1 (UTA1) are vasopressin‐regulated genes in normal renal inner medullas. However, we previously reported that 7 day dDAVP regulated AQP2 expression is impaired in the renal inner medulla (IM) of AQP1 null mice with urinary concentrating defect. In the present study, we investigated the regulation of UTA1 and UTA3 in 7day dDAVP infused AQP1 null mice. We found that 7 day dDAVP increases the expression of UTA1 and UTA3 proteins to 212 ± 40.4% vs. control 100 ± 19.5% and 588 ± 93.7% vs. control 100 ± 34.4%, respectively, which are similar to the results from dDAVP infused wild type mice. 7 day dDAVP also increases the expression of endoplasmic reticulum (ER) stress genes in IM of AQP1 null mice. GRP78 mRNA increases by 1.74 fold and protein increases by 2 fold compared to that in control 7 days after dDAVP infusion. Immunohistochemistry demonstrates that 7 day dDAVP causes GRP78 protein localize on the apical membrane of collecting duct cells in the papillary tip of IM with AQP2. Electron microscopy of immuno‐gold staining confirms the apical location of GRP78. Moreover, 7 day dDAVP increases GADD153 mRNA to 2.93 ± 0.13 and ATF4 mRNA to 1.55 ± 0.06 compared to those in controls 1 ± 0.05 and 1 ± 0.06, respectively, in IM of AQP1 null mice. Conclusion: in renal IM of AQP1 null mice 1) the regulation of UTA1 and UTA3 by dDAVP is intact and 2) 7 day dDAVP activates ER stress pathway.