Aldosterone-mediated apical targeting of ENaC subunits is blunted in rats with streptozotocin-induced diabetes mellitus.
Background: Diabetes mellitus (DM) is associated with a significant polyuria and natriuesis as well as increased plasma aldosterone and anti-diuretic hormone arginine vasopressin (AVP). This study aimed to determine whether diabetic kidneys compensate for the urinary sodium and water losses by increasing apical targeting of epithelial sodium channel (ENaC) subunits and aquaporin-2 (AQP2) in the collecting duct, in addition to the previously observed changes in ENaC subunit protein expression in different kidney zones.
Methods: Female rats were investigated 2 weeks after induction of DM by streptozotocin administration. Kidneys were examined by immunohistochemisty and semiquantitative immunoblotting.
Results: We demonstrated that the protein expression of renal AQP2, Ser-256 phosphorylated AQP2, AQP3, beta- and gamma-ENaC (but not alpha-ENaC) increased consistently with an increased AVP response. In contrast, there were no significant changes in the relative apical targeting of beta-, gamma- and alpha-ENaC, and the shift in the molecular weight of gamma-ENaC from 85 kDa to 70 kDa was not observed despite increased plasma aldosterone levels. These results were supported by changes in the functional data showing increased solute-free water reabsorption, increased fractional excretion of sodium and an unchanged ratio of potassium to sodium in the urine.
Conclusions: The data demonstrate that diabetic kidneys have a reduced sensitivity to the anti-natriuretic action of elevated plasma aldosterone levels with no relative increase in ENaC subunit apical targeting, whereas there is increased expression of beta- and gamma-ENaC, which alone may play a role in the increased sodium reabsorption in the kidney in DM.
Danish Medical Research Council
The Karen Elise Jensen Foundation
The WIRED program (Nordic Centre of Excellence in Molecular Medicine)
European Commission FP6 via the RTN ‘AQUAGLYCEROPORINS’ (project 035995-2)
Korea Science and Engineering Foundation grant funded by the MOST (R01-2007-000-20441-0)
Brain Korea 21 projects in 2006
CommentsThis is a pre-copyedited, author-produced PDF of an article accepted for publication in Nephrology Dialysis Transplantation following peer review. The version of record O'Neill H, Lebeck J, Collins PB, Kwon TH, Frøkiaer J, Nielsen S. Aldosterone-mediated apical targeting of ENaC subunits is blunted in rats with streptozotocin-induced diabetes mellitus. Nephrol Dial Transplant. 2008 ;23(5):1546-55. is available online at: https://academic.oup.com/ndt/article/23/5/1546/1805824
Published CitationO'Neill H. et al. Aldosterone-mediated apical targeting of ENaC subunits is blunted in rats with streptozotocin-induced diabetes mellitus. Nephrol Dial Transplant. 2008 ;23(5):1546-55.
Publication Date19 November 2007
- School of Pharmacy and Biomolecular Sciences
- Accepted Version (Postprint)