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
| Title: | 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 |
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| Authors: | Kim, Gheun-Ho; Lee, Jay Wook; Oh, Yun Kyu; Chang, Hye Ryun; Joo, Kwon Wook; Na, Ki Young; Earm, Jae-Ho; Knepper, Mark; Han, Jin Suk |
| Publisher: | Journal of the American Society of Nephrology |
| Date Published: | November 01, 2004 |
| Reference Number: | 666 |
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.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
However, whether NDI is acquired or inherited, the treatment regime – low sodium diet along with taking thiazides – is the same. Paradoxically, thiazides are diuretics. That is, they are meant to increase urine output. Since one of the expressions of NDI is excessive urination, it might seem odd that thiazide diuretics are used to decrease urine flow.
Kim, et al., conducted research to clarify the molecular dynamics involved in the antidiuretic action of the thiazide diuretic, hydrochlorothiazide (HCTZ). First, they induced NDI in an experimental group of rats by feeding them lithium laced food. As expected, this rat group developed NDI and began to void large amounts of dilute urine. These rats were divided into two groups. Inserted into each rat in one group was a pump that delivered HCTZ. The pumps in the other group delivered placebo.
After a set time, the researchers examined the kidney tissue of both groups. They found that the HCTZ treated group had significantly more AQP2 in the principal cells of their kidney collecting duct. AQP2 is vital for urine concentration as it allows water to enter the cells. Lithium reduces the amount of AQP2 in the cell, but HCTZ appears to be able to inhibit the lithium induced AQP2 reduction.
The researchers also discovered that HCTZ treatment also increased the number of several major sodium transporters found on specific regions of the kidney, specifically, the Na-CL co-transporter and the epithelial sodium channel, which enhances sodium re-absorption in the kidney. The researchers speculated that this increase was due to an HCTZ stimulated release of aldosterone in the treated rats.
The researchers conclude that the increase of AQP2 and the kidney sodium transporters stimulated by HCTZ may explain how HCTZ induces a decrease in the excessive urine output associated with NDI.