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O'Neill, Heidi,Lebeck, Janne,Collins, Patrick B,Kwon, Tae-Hwan,Frøkiaer, Jørgen,Nielsen, Søren Springer International ; Oxford University Press 2008 Nephrology, dialysis, transplantation Vol.23 No.5
<P>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.</P>
Jung, Hyun Jun,Kim, Sang-Yeob,Choi, Hyo-Jung,Park, Eui-Jung,Lim, Jung-Suk,Frøkiaer, Jørgen,Nielsen, Søren,Kwon, Tae-Hwan American Physiological Society 2015 American journal of physiology. Renal physiology Vol.308 No.5
<P>Aquaporin-2 (AQP2) mediates arginine vasopressin (AVP)-induced water reabsorption in the kidney collecting duct. AVP regulates AQP2 expression primarily via G(s)alpha/cAMP/PKA signaling. Tankyrase, a member of the poly(ADP-ribose) polymerase family, is known to mediate Wnt/beta-catenin signaling-induced gene expression. We examined whether tankyrase plays a role in AVP-induced AQP2 regulation via ADP-ribosylation of G protein-alpha (G alpha) and/or beta-catenin-mediated transcription of AQP2. RT-PCR and immunoblotting analysis revealed the mRNA and protein expression of tankyrase in mouse kidney and mouse collecting duct mpkCCDc14 cells. dDAVP-induced AQP2 upregulation was attenuated in mpkCCDc14 cells under the tankyrase inhibition by XAV939 treatment or small interfering (si) RNA knockdown. Fluorescence resonance energy transfer image analysis, however, revealed that XAV939 treatment did not affect dDAVP-or forskolin-induced PKA activation. Inhibition of tankyrase decreased dDAVP-induced phosphorylation of beta-catenin (S552) and nuclear translocation of phospho-beta-catenin. siRNA-mediated knockdown of beta-catenin decreased forskolin-induced AQP2 transcription and dDAVP-induced AQP2 expression. Moreover, inhibition of phosphoinositide 3-kinase/Akt, which was associated with decreased nuclear translocation of beta-catenin, diminished dDAVP-induced AQP2 upregulation, further indicating that beta-catenin mediates AQP2 expression. Taken together, tankyrase plays a role in AVP-induced AQP2 regulation, which is likely via beta-catenin-mediated transcription of AQP2, but not ADP-ribosylation of G alpha. The results provide novel insights into vasopressin-mediated urine concentration and homeostasis of body water metabolism.</P>