2004 Global Researcher Conference Proceeding
April 09 - 11, 2004
| Conference: | 2004 Global Researcher Conference |
|---|---|
| Title: | Effects of Carbenoxolone on Sodium Transporter and Aquaporin-2 Abundance in Kidney |
| Authors: | Packer, Randall; Schnor, Nils; Shannon, Thomas; Knepper, Mark |
| Institutions: | National Institutes of Health, George Washington University |
The enzyme 11b-hydroxysteroid dehydrogenase (11b-HSD2) catalytic activity and abundance are increased by vasopressin. In aldosterone target cells 11b-HSD2 oxidizes glucocorticoids, preventing them from binding to, and from inappropriately stimulating mineralocorticoid receptors. Inhibition of 11b-HSD2 action causes hypertension, presumably by increasing sodium and water retention. To determine the effects of 11b-HSD2 inhibition on the abundance of sodium transporters and aquaporin-2, male rats were fed the 11b-HSD2 inhibitor carbenoxolone (CBX- 100 mg/kg/day) for 6 days and systolic blood pressure was monitored using a tail cuff system. Rats were fed a gel food diet to control water and salt intake. On the sixth day of treatment, systolic pressure of CBX treated rats increased to 139 ± 12 mm Hg compared to 108 ± 9 mm Hg for controls. CBX treatment had no significant effect on serum Na+ or total urinary Na+ and K+ excretion. Immunoblots of whole kidney homogenates showed that CBX treatment did not significantly affect abundance of Na/K ATPase, NHE3 or NKCC2 but it caused increases in a-ENaC (216%) and b-ENaC (256 %) and a decrease to 33% of control of g-ENaC. Abundance of NCC increased to 228% of control. Aquaporin-2 abundance increased to 173 % of control in CBX treated rats. The observed increases in a-ENaC and NCC are consistent with glucocorticoid stimulation of mineralocorticoid receptors as a result of 11b-HSD2 inhibition. The results indicate that the effects of vasopressin to increase NCC, a-ENaC, b-ENaC and AQP2 levels are not due to the associated changes in 11b-HSD2 activity, which would be expected to have the opposite effect on the transporters. Rather, it appears that the effect of vasopressin to increase 11b-HSD2 activity would be expected to moderate vasopressin’s effect on transporter expression and salt and water retention.
The presence of the hormone, vasopressin (AVP) increases the activity and amount of 11 beta-hydroxysteroid dehydrogenase (11b-HSD2). Packer, et al., wondered what would happen to the number of sodium transporters (Na/K ATPase, NHE3, NCC, NKCC2, a-ENaC, b-ENaC, g-ENaC) and the number of AQP2s if 11b-HSD2 were prevented from doing its job. They treated an experimental group of rats with 11b-HSD2 inhibition and found that this increased the rats’ blood pressure, but had no effect on the amount of sodium in their blood or sodium and potassium in their urine. 11b-HSD2 inhibition did not affect the amount of Na/K ATPase, NHE3 or NKCC2. It did increase NCC a-ENaC and b-ENaC, while it decreased g-ENaC. The abundance of AQP2 increased. The increase in NCC and the changes in abundance of the ENaC subunits show that when 11b-HSD2 is inhibited, glucorticoids mimic the effect of aldsosterone and cause high blood pressure. The increased AQP2 seen when 11b-HSD2 is inhibited suggests that the normal effect of vasopressin to increase 11b-HSD2 activity moderates vasopressin’s effects to increase salt and water retention.