Phenotypes Developed in Secretin Receptor-Null Mice Indicated a Role for Secretin in Regulating Renal Water Reabsorption
| Title: | Phenotypes Developed in Secretin Receptor-Null Mice Indicated a Role for Secretin in Regulating Renal Water Reabsorption |
|---|---|
| Authors: | Chu, Jessica Y. S.; Chung, Samuel C. K.; Lam, Amy K. M.; Tam, Sidney C.F.; Chung, Sookja K.; Chow, Billy K. C. |
| Publisher: | Molecular and Cellular Biology |
| Date Published: | April 01, 2007 |
| Reference Number: | 720 |
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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)
Aquaporin-2 (AQP2) is a protein that plays an important role in the kidney’s ability to reabsorb water and therefore concentrate urine. When the hormone, arginine vasopressin (AVP), binds with the vasopressin-2 receptor (V2R) on the membrane of the principal cells of the kidney collecting duct, it initiates a chemical sequence that results in AQP2 traveling from the cell interior to a section of the cell membrane called the apical membrane. Once inserted into the apical membrane, AQP2 acts as a channel through which water can enter the cell. When AVP leaves, the AQP2 moves from the apical membrane back into the cell interior.
People with Nephrogenic Diabetes Insipidus (NDI) are unable to respond to AVP, either because of a mutation in the AQP2 gene or the V2R gene. In either case, AQP2 is not able to travel to the apical membrane to act as a water channel. However, researchers are beginning to discover that there are mechanisms within the body that insert AQP2 into the cell membrane (as well as help keep its numbers up) that operate independently of AVP. Chu, et al., hypothesized that secretin, a hormone that controls the cellular transportation of electrolytes, is one such AVP-independent mechanism that aids AQP2 in its movement from the cell interior to the apical membrane of the kidney collecting duct principal cells.
To test their hypothesis, the research team first had to generate a line of mice lacking the secretin receptor (SCTR). Without SCTR, there is nothing for the hormone, secretin, to bind with on the cell membrane. Therefore, the chemical sequence it would normally initiate does not occur. After creating a mutant SCTR gene to produce non-functioning SCTRs, the researchers created a line of transgenic mice which bore, as expected, mice with two normal SCTR genes, mice with one normal and one mutant SCTR gene, and mice with two mutant SCTR genes. The latter type of mice (SCTR-/-) are called SCTR knockout mice and have no functional SCTRs.
Clinically, these mice showed no growth abnormality, but their kidney/body weight ratio was significantly higher than their normal littermates. Also, the SCTR-/- mice kidneys were abnormal, suggesting that their kidneys might have altered water absorption and filtration processes. They voided high volumes of dilute urine, exhibited excessive thirst, showed reduced urinary excretions of sodium and potassium, and reduced urea and creatinine levels in their urine. In short, they showed many of the clinical symptoms of NDI, even though they had high AVP levels.
Further investigation revealed that the level of transcripts (strands of messenger RNA) for secretin, AQP2 and AQP4 were reduced in the SCTR-/- mice kidneys. However, these mice showed normal transcript levels of V2R. This showed that the impaired ability to concentrate urine in the SCTR-/- mice was not due to reduced levels of V2R, but to reductions in AQP2 and AQP4. Examining the kidneys of normal mice (SCTR+/+) showed SCTR, along with V2R, throughout the kidney interior. SCTR is found mostly on a section of the cell membrane called the basolateral membrane, whereas AQP2 is found in the apical membrane. SCTR was also found in sections of the kidney associated with sodium reabsorption, the proximal tubules and the ascending thick segment of the loop of Henle.
Chu, et al., thought the SCTR might mimic the effect of AVP on AQP2’s movement from the cell interior to the apical membrane. To test this, they examined the effects of SCTR on the distribution of AQP2 in the kidney tubular cells of both SCTR-/- and SCTR+/+ mice. In the SCTR+/+ mice, secretin induced a dose-dependent increase in AQP2 in the cells. Secretin had no such effect on the SCTR-/- mice. This indicates that secretin induces its effects upon binding with its receptor.
Chu, et al., examined the movement and expression of AQP2 in the dehydrated mice. The SCTR-/- mice showed less reduced numbers of AQP2 and less movement of AQP2 to the apical membrane than the normal mice, which showed an increase in the numbers of AQP2 and their movement to the cell membrane. This demonstrates that SCTR is at least partially responsible for the increase in the amount of AQP2s and their movement to the cell membrane under conditions of dehydration.
The researcher’s data strongly suggest that secretin plays an AVP-independent role in the expression and movement of AQP2s in the kidney. This could be of great interest to the NDI community as it shows a direction of study for developing therapies to treat NDI that are independent of the AVP pathway.