How does someone get NDI from taking Lithium?
|Author:||Bichet, Daniel G.|
First, the antidiuretic hormone, arginine vasopressin (AVP) binds with its vasopressin-2 receptors located in the basolateral membranes of the principal cells of the kidney collecting ducts. This bond stimulates the enzyme, adenylyl cyclase (AC). AC, in turn, elevates the levels of cyclic adenosine monophosphate (cAMP) inside the principal cells. cAMP activates protein kinase A (PKA) which, through a series of steps that are not yet entirely clear, induces aquaporin-2s (AQP2s) to travel to the principal cell's apical membrane. Once the AQP2s are inserted into the apical membrane, they act as channels through which much more water can cross the apical membrane than usual. The insertion of AQP2s is what allows the kidney to reabsorb the water flowing through the collecting ducts. When AVP absents itself from the cell, the AQP2s are removed from the apical membrane, brought back inside the cell, and the apical membrane returns to its normal level of low water permeability.
Lithium causes a dramatic decrease in the numbers of AQP2 expressed in the principal cells. This decrease is paralleled by a progressive development of severe polyuria. Of the few AQP2s that do get expressed in the presence of lithium, very few are able to travel to the apical membrane where they must be if they are to perform their function of letting water flow across the membrane. Lithium has been shown to impair the production of cAMP in CD cells, and it is likely that reduced cAMP is, in part, responsible for the reduced numbers of AQP2 found in patients with lithium-induced NDI.
Animal studies have shown that lithium decreases cAMP concentration by blocking the activation of adenylyl cyclase. Lithium may also decrease cAMP levels by increasing its destruction by phosphodiesterase. Lithium has been shown to increase the ability of AVP to produce prostaglandin E2 in the kidney medulla. This also results in increased urination.