Antidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium channel.
Thiazides have been used in patients with nephrogenic diabetes insipidus (NDI) to decrease urine volume, but the mechanism by which it produces the paradoxic antidiuretic effect remains unclear. Previous studies have reported that downregulation of aquaporin-2 (AQP2) is important for the development of lithium-induced (Li-induced) polyuria and that hydrochlorothiazide (HCTZ) increases renal papillary osmolality and Na(+) concentration in Brattleboro rats. For elucidating the molecular basis of the antidiuretic action of HCTZ in diabetes insipidus, whether administration of HCTZ may affect the expression of AQP2 and major renal Na(+) transporters in Li-induced NDI rats was investigated, using semiquantitative immunoblotting and immunohistochemistry. After feeding male Sprague-Dawley rats Li chloride-containing rat diet for 4 wk, HCTZ or vehicle was infused subcutaneously via osmotic minipump. Urine output was significantly decreased by HCTZ treatment, whereas it was not changed in vehicle-treated rats. Urine osmolality was also higher in HCTZ-treated rats than in vehicle-treated rats. Semiquantitative immunoblotting using whole-kidney homogenates revealed that HCTZ treatment caused a significant partial recovery in AQP2 abundance from Li-induced downregulation. AQP2 immunohistochemistry showed compatible findings with the immunoblot results in both cortex and medulla. The abundances of thiazide-sensitive NaCl co-transporter and alpha-epithelial sodium channel were increased by HCTZ treatment. Notably, HCTZ treatment induced a shift in molecular weight of gamma-epithelial sodium channel from 85 to 70 kD, consistent with previously demonstrated aldosterone stimulation. The upregulation of AQP2 and distal renal Na(+) transporters in response to HCTZ treatment may account for the antidiuretic action of HCTZ in NDI.
Kim
Gheun-Ho
GH
Department of Internal Medicine and Institute of Biomedical Sciences, Hanyang University College of Medicine, Seoul, Korea.
Lee
Jay Wook
JW
Oh
Yun Kyu
YK
Chang
Hye Ryun
HR
Joo
Kwon Wook
KW
Na
Ki Young
KY
Earm
Jae-Ho
JH
Knepper
Mark A
MA
Han
Jin Suk
JS
D000818:Animals; D051399:Aquaporin 2; D020346:Aquaporins / Q000378:metabolism*; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000503:physiopathology*; D004231:Diuresis / Q000187:drug effects*; D004334:Drug Administration Schedule; D053503:Epithelial Sodium Channels; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000494:pharmacology*; D008094:Lithium; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000378:metabolism*; D015854:Up-Regulation
C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D020346:Aquaporins; D053503:Epithelial Sodium Channels; D011955:Receptors, Drug; C578876:Slc12a3 protein, rat; D015222:Sodium Channels; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; C064415:thiazide receptor; D006852:Hydrochlorothiazide; D008094:Lithium