Cellular Mechanism of Lithium-Induced Nephrogenic Diabetes Insipidus in Rats
| Title: | Cellular Mechanism of Lithium-Induced Nephrogenic Diabetes Insipidus in Rats |
|---|---|
| Authors: | Yamaki, Mario; Kusano, Eiji; Tetsuka, Toshifumi; Takeda, Shigeyuki; Homma, Sumiko; Murayama, Naoki; Asano, Yasushi |
| Publisher: | American Journal of Physiology |
| Date Published: | September 01, 1991 |
| Reference Number: | 317 |
One of the mechanisms by which Li evokes polyuria is thought to be impairment of arginine vasopressin (AVP)-sensitive adenylate cyclase (AdC) in cells of the renal collecting duct. To investigate how AdC is influenced by chronic administration of Li, we created nephrogenic diabetes insipidus (NDI) in rats and microdissected the medullary collecting tubule from both control and NDI rats. In the NDI group, the 10(-6) M AVP-stimulated cAMP contents failed to increase completely, and the levels were significantly lower than that of the control group (10.4 +/- 1.4 vs. 48.4 +/- 4.7 fmol/mm, P less than 0.001). Pretreatment with pertussis toxin (PT), an inhibitor of inhibitory G protein (Gi), did not affect the basal cAMP levels in both groups, although it increased AVP-stimulated cAMP production in the NDI group in a dose- and time-dependent manner. AVP-stimulated cAMP production with over 100 ng/ml PT in the NDI group reached the levels observed in the control group. Incubation with cholera toxin, an agonist of stimulatory G protein (Gs), increased the cAMP content in the two groups to almost equal levels. To exclude the possibility that prostaglandin E2 (PGE2) is involved in the cellular mechanism of Li-induced NDI, the effect of indomethacin (Indo) on PT action was examined. However, Indo (10(-5) M) did not influence either the basal or AVP-dependent cAMP contents. From these results it is suggested that Li impairs AVP-sensitive AdC not through inhibition of Gs but through activation of Gi and that PGE2 may not be involved in the cellular pathogenesis of NDI at least in the rat at the step of cAMP formation.
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)
The MCTs, located in the kidneys, contain the principal cells of the kidney collecting duct. These cells contain the cellular mechanism that allows the kidney to concentrate urine and to reabsorb the body water that flows through its collecting ducts. This is how the mechanism works: the antidiuretic hormone, arginine vasopressin (AVP), binds with the vasopressin-2 receptor (V2R) located in the collecting duct cells. The bound AVP/V2R couples to a stimulatory G protein (Gs). This stimulates adenylate cyclase (AdC), which elevates cAMP. Elevated levels of cAMP are necessary to signal the water-transporting protein called aquaporin-2 (AQP2) to be inserted into the apex of the collecting duct cell membranes. This makes the cells more water permeable, and this is how the kidneys are able to reabsorb water through and concentrate urine in the collecting ducts.
Previous research indicated that Li impairs AVP-sensitive AdC. AdC is made up of three subunits: a receptor, a G protein, and a catalytic unit. The researchers prepared the dissected tubules in three different ways in order to clarify how Li effects AdC:
- They incubated some MCTs in pertussis toxin (PT) to prevent the inhibitory action of the inhibitory G protein (Gi).
- They incubated some of the MCTs in cholera toxin (CT) to promote the stimulatory action of the stimulatory G protein (Gs).
- They incubated some of the MCTs in indomethacin (Indo) to inhibit the actions of prostaglandin cyclooxygenase and suppress the synthesis of PGE2. Control MCTs were similarly prepared and all the samples were measured to see how much cAMP they generated. The amount of cAMP generated would show whether the MCTs were or were not capable of allowing urine to be concentrated and water reabsorbed.
The results of their investigation confirmed that the cellular mechanism involved in the pathogenesis of Li-induced NDI is based on the impairment of AdC. It does this, not by inhibiting Gs, but by activating Gi. In this study, PGE2 was found to have no impairing effect on AdC.