Congestive Heart Failure in Rats is Associated with Increased Expression and Targeting of Aquaporin-2 Water Channel in Collecting Duct
| Title: | Congestive Heart Failure in Rats is Associated with Increased Expression and Targeting of Aquaporin-2 Water Channel in Collecting Duct |
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| Authors: | Marples, David; Knepper, Mark; Nielsen, Soren; Terris, Ph.D., James M.; Andersen, Ditte; Frokiaer, Jorgen; Jonassen, Thomas E.; Petersen, Jorgen S.; Ecelbarger, Ph.D., Carolyn |
| Publisher: | Proceedings of the National Academy of Sciences of the United States of America |
| Date Published: | May 01, 1997 |
| Reference Number: | 195 |
We tested whether severe congestive heart failure (CHF), a condition associated with excess free-water retention, is accompanied by altered regulation of the vasopressin-regulated water channel, aquaporin-2 (AQP2), in the renal collecting duct. CHF was induced by left coronary artery ligation. Compared with sham-operated animals, rats with CHF had severe heart failure with elevated left ventricular end-diastolic pressures (LVEDP): 26.9 +/- 3.4 vs. 4.1 +/- 0.3 mmHg, and reduced plasma sodium concentrations (142.2 +/- 1. 6 vs. 149.1 +/- 1.1 mEq/liter). Quantitative immunoblotting of total kidney membrane fractions revealed a significant increase in AQP2 expression in animals with CHF (267 +/- 53%, n = 12) relative to sham-operated controls (100 +/- 13%, n = 14). In contrast, immunoblotting demonstrated a lack of an increase in expression of AQP1 and AQP3 water channel expression, indicating that the effect on AQP2 was selective. Furthermore, postinfarction animals without LVEDP elevation or plasma Na reduction showed no increase in AQP2 expression (121 +/- 28% of sham levels, n = 6). Immunocytochemistry and immunoelectron microscopy demonstrated very abundant labeling of the apical plasma membrane and relatively little labeling of intracellular vesicles in collecting duct cells from rats with severe CHF, consistent with enhanced trafficking of AQP2 to the apical plasma membrane. The selective increase in AQP2 expression and enhanced plasma membrane targeting provide an explanation for the development of water retention and hyponatremia in severe CHF.
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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.
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AQP2 is essential for the kidney to be able to reabsorb the water flowing through the kidney collecting duct. It is also essential for the kidney to be able to concentrate urine. Thus, AQP2 serves to help the kidney maintain body water balance by allowing it to reabsorb water through its collecting ducts.
Water reabsorption in the collecting duct is regulated both by short-term and long-term mechanisms, both of which involve VP and AQP2. Short-term regulation occurs when AQP2, in response to VP, inserts itself into the apex of collecting duct cell membranes. Long-term regulation of water reabsorption depends on long-term regulation of AQP2, which is largely dependent on the concentration of VP circulating through the body.
Defective long-term regulation of AQP2, expressed as a lower amount of AQP2s than needed, plays a key role in water balance disorders such as acquired nephrogenic diabetes insipidus (NDI). In this study, Nielsen, et al., show that defective short- and long-term regulation of AQP2 are associated with severe congestive heart failure (CHF). CHF is associated with a body water imbalance caused by the body retaining an excess of free water (that portion of the body water which is not bound by macromolecules or organelles).
The authors induced CHF in rats by binding their left coronary artery. This caused the rats to have severe heart failure with elevated left ventricular end diastolic pressure (LVEDP) and reduced sodium concentrations in the blood. When the authors examined the kidney tissue of the CHF rats, they found a marked increase in the amount of AQP2s. Further, most of the AQP2 was in the apex of the cell membrane. The control rats had no increase in AQP2s and their AQP2s were found more within the cell cytoplasm and less prominently in the apex of the cell membrane.
These findings indicate an abnormal regulation of AQP2 associated with CHF. That is, there were too many AQP2s and they were mostly located in the cell membranes where they were acting as water channels. This would result in the collecting duct cell membranes being highly water permeable, causing too much water to be reabsorbed and retained by the body. This explains both the free-water retention and low concentration of sodium in the blood associated with CHF. The authors suggest that this abnormal regulation of AQP2s was caused by chronically increased circulating levels of VP which are known to occur in CHF.