Downregulation of UT-A1/UT-A3 is associated with urinary concentrating defect in glucocorticoid-excess state.
Excessive glucocorticoid hormone, as occurs with Cushing syndrome, is known to be associated with altered body water homeostasis, but the molecular mechanisms are unknown. In this study, rats treated with daily dexamethasone (Dex) for 14 d provided a model of Cushing syndrome. Compared with control rats, Dex-treated rats demonstrated increased mean arterial pressure, urine flow rate, and urinary excretion of both sodium and urea. Dex-treated rats had increased abundance of aquaporin 1 (AQP1), AQP3, and Na-K-2Cl co-transporter proteins and a marked reduction of the urea transporters UT-A1 and UT-A3. In response to an acute water load, Dex-treated rats increased water excretion more than control rats, but both groups exhibited similar AQP2 expression. In response to fluid deprivation, Dex-treated rats demonstrated an impaired urinary concentrating capacity: Urine flow rate was higher and urine osmolality was lower than control rats despite an increase in AQP1, AQP3, and Na-K-2Cl co-transporter expression. AQP2 expression was similar between the two groups, but UT-A1 and UT-A3 were decreased and urinary urea excretion was increased in Dex-treated rats. Because Dex-treated rats ingested less food and water compared with controls, paired food and water studies were performed; these substantiated the previous results. In summary, the alterations in body water observed with glucocorticoid excess may be a result, in part, of impaired urinary concentrating capacity; downregulation of UT-A1 and UT-A3 and increased urea excretion may contribute to this impairment.
Li
Chunling
C
Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Wang
Weidong
W
Summer
Sandra N
SN
Falk
Sandor
S
Schrier
Robert W
RW
D000818:Animals; D003480:Cushing Syndrome / Q000378:metabolism* / Q000503:physiopathology*; D003907:Dexamethasone; D004195:Disease Models, Animal; D004231:Diuresis / Q000502:physiology; D007671:Kidney Concentrating Ability / Q000502:physiology*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000652:urine; D000096982:Urea Transporters
D003907:Dexamethasone; D026901:Membrane Transport Proteins; D014508:Urea; D000096982:Urea Transporters