A Variant of Nephrogenic Diabetes Insipidus: V2 Receptor Abnormality Restricted to the Kidney
|Title:||A Variant of Nephrogenic Diabetes Insipidus: V2 Receptor Abnormality Restricted to the Kidney|
|Authors:||Knoers, Nine; Monnens, Leo A.H.|
|Publisher:||European Journal of Pediatrics|
|Date Published:||March 01, 1991|
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)
In addition to changes in the kidney, DDAVP induces physiological changes in blood dynamics and chemistry: it releases plasminogen activator and two blood coagulation factors (Factor VIIc and von Willebrand factor), and it dilates blood vessels, as manifested by facial flushing, a fall in the diastolic blood pressure and a rise in pulse rate. This has led some researchers to suggest that the receptor to which AVP binds in the kidney, the vasopressin-2 receptor (V2R), is located outside the kidney as well as inside it.
Many researchers believe that a faulty V2R is the molecular basis of CNDI. They suggest that for some reason AVP is unable to bind with V2R, so the hormonal message that AVP has for the kidneys, "concentrate urine and reabsorb water flowing through the collecting ducts," can't get through. Most CNDI patients do not respond to DDAVP either inside or outside the kidney. That is, infusions of DDAVP in CNDI patients generally induce no change in kidney concentrating power or in blood dynamics or chemistry. This leads some researchers to posit a general V2R defect in these patients.
However, in their paper, Knoers and Monnens report a four-year old boy with severe CNDI who did show distinct responses to DDAVP in terms of blood dynamics and chemistry, even though he did not respond to it in terms of the kidney. Other researchers have reported on CNDI patients with similar responses to DDAVP. The authors state that this shows that CNDI may be produced by mutations of more than just one gene.
The bulk of scientific research up to 1991 points to defective V2Rs as the likely cause of CNDI. However, when AVP binds with V2R, it initiates a molecular sequence involving several different types of proteins, anyone of which could theoretically be defective and therefore prevent the completion of the sequence. For example, the V2R is coupled to a G protein. This could be faulty. The G protein helps bound the AVP/V2R couple to the enzyme, adenylyl cyclase (AdC). This could be defective. AdC elevates cellular levels of the important metabolic regulator, cyclic adenosine monophosphate (cAMP). This could be at fault, or the cause could be somewhere in the sequence after cAMP, say in the water-transporting protein that makes the collecting duct cell permeable enough to reabsorb the required amount of body water.
If, as is most likely, the NDI-causing defect lies in the V2R, there is a possibility that in the author's patient the V2R inside the kidney is different than those V2Rs outside the kidney. And whereas most people with CNDI have a general V2R abnormality, this patient just has an abnormality of the V2Rs in his kidney.