Dexamethasone increases aquaporin-2 protein expression in ex vivo inner medullary collecting duct suspensions

Abstract

Aquaporin-2 (AQP2) is the vasopressin-regulated water channel that controls renal water reabsorption and plays an important role in the maintenance of body water homeostasis. Excessive glucocorticoid as often seen in Cushing's syndrome causes water retention. However, whether and how glucocorticoid regulates AQP2 remains unclear. In this study, we examined the direct effect of dexamethasone on AQP2 protein expression and activity. Dexamethasone increased AQP2 protein abundance in rat inner medullary collecting duct (IMCD) suspensions. This was confirmed in HEK293 cells transfected with AQP2 cDNA. Cell surface protein biotinylation showed an increase of dexamethasone-induced cell membrane AQP2 expression and this effect was blocked by glucocorticoid receptor antagonist RU486. Functionally, dexamethasone treatment of oocytes injected with an AQP2 cRNA increased water transport activity as judged by cell rupture time in a hypo-osmotic solution (66 ± 13 s in dexamethasone vs. 101 ± 11 s in control, n = 15). We further found that dexamethasone treatment reduced AQP2 protein degradation, which could result in an increase of AQP2 protein. Interestingly, dexamethasone promoted cell membrane AQP2 moving to less buoyant lipid raft submicrodomains. Taken together, our data demonstrate that dexamethasone promotes AQP2 protein expression and increases water permeability mainly via inhibition of AQP2 protein degradation. The increase in AQP2 activity promotes water reabsorption, which may contribute to glucocorticoid-induced water retention and hypertension.

Effects of gonadectomy and testosterone treatment on aquaporin expression in the kidney of normotensive and hypertensive rats

“…10,11 Exaggerated AQP expression in kidneys can result in H 2 O retention as observed in hypothyroidism and in glucocorticoid-induced hypertension. 12,13 Thirteen AQP isoforms have been identified in mammals and are classified into classical AQPs and aquaglyceroporins, based on the pore selectivity.…”

Different Effects of Tolvaptan in Patients with Idiopathic Membranous Nephropathy with Nephrotic Syndrome

“…Chen et al reported the findings from an ex vivo study using suspensions of kidney inner medullary collecting duct cells that showed that dexamethasone directly upregulated the expression of cellular AQP-2. This suggested that dexamethasone may improve the responsiveness to tolvaptan by increasing AQP-2 expression (7). Therefore, there may be additional and favorable effects of PSL treatment for non-responders to tolvaptan, such as in Case 2.…”

“…Aquaporin (AQP)-2, a protein expressed in the apical membranes of the principal cells of the renal collecting duct, regulates water-absorption and plays a pivotal role in maintaining water-homeostasis (7). Imamura et al reported the urinary AQP-2 level to be a novel predictor of the response to tolvaptan in patients with decompensated heart failure (1).…”

Modulation of kidney urea transporter UT-A3 activity by alpha2,6-sialylation

“…Different glycosylation is mainly due to different processing after α-mannosidase digestion by the sequential action of specific glycosyltransferases (17, 36). As seen in many transporter proteins (1, 9), UT-A3 is highly glycosylated with two forms due to different extent of glycosylation. We for the first time verified that the 65 kDa UT-A3 is the mature glycosylation form contained poly-LacNAc..…”