Aldosterone-mediated apical targeting of ENaC subunits is blunted in rats with streptozotocin-induced diabetes mellitus.

Heidi O'Neill, University of Aarhus
Janne Lebeck, University of Aarhus
Patrick B Collins, Royal College of Surgeons in Ireland
Tae-Hwan Kwon, University of Aarhus
Jorgen Frokiaer, University of Aarhus
Soren Nielsen, University of Aarhus

Document Type Article

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Nephrology Dialysis Transplantation following peer review. The definitive publisher-authenticated version Nephrology Dialysis Transplantaion 2008 May;23(5):1546-55 is available online at: http://ndt.oxfordjournals.org/cgi/content/full/23/5/1546. doi: 10.1093/ndt/gfm814.

Abstract

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.