Acquired Diabetes Insipidus
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Acquired NDI
Acquired NDI is the consequence of several conditions (Table 2) that are characterized by an increased water output and reduced urine osmolality, despite elevated levels of AVP. In many of these conditions, the kidney is unable to handle water due to an impaired responsiveness to vasopressin. As discussed below, a number of rat models with NDI have been evaluated, and common for all is a reduced expression of AQP2 in the principal cells of the collecting ducts. However, as is discussed, the degree of AQP2 downregulation as well as the intracellular localization of the protein differs significantly among the various conditions, suggesting that different mechanisms are responsible for AQP2 dysregulation in the various models. In addition to DI, a few other serious conditions are associated with reduced AQP2 levels and urinary concentrating defects (see Table 2).
1. Lithium-induced NDI
Lithium administration is a very common treatment of manic-depressive disease. It is estimated that 1 in 1,000 of the population receive lithium, and roughly 20-30% of these develop serious side effects including polyuria (16, 39) primarily due to a vasopressin-resistant urinary-concentrating defect, i.e., NDI. We examined the effect of oral lithium treatment of rats for 25 days. AQP2 and AQP3 levels were progressively reduced to ~5% of levels in control rats after 25 days of lithium treatment (129, 149). The downregulation of AQP2 expression was paralleled by a progressive development of severe polyuria. With serum lithium levels in the therapeutic range, rats produced a daily urine output that matched their own weight (149). In addition, quantitative immunoelectron microscopy of AQP2 labeling in the IMCD principal cells showed that there was a reduction in AQP2 in the apical plasma membrane, as well as in the basolateral plasma membrane and intracellular vesicles. Thus reduction of AQP2 in both the apical and the basolateral plasma membrane may participate in the overall reduced water reabsorption (149). The reduced AQP3 expression was also confirmed by immunocytochemistry (129). Thus downregulation of both AQP2 and AQP3 appears to play a significant role in the development of lithium-induced polyuria. The reduction in AQP2 (and AQP3) expression may be caused by a lithium-induced impairment in the production of cAMP in collecting duct principal cells (38, 39), indicating that inhibition of cAMP production may in part be responsible for the reduction in AQP2 expression as well as the inhibition of targeting to the plasma membrane in response to lithium treatment. This is consistent with the presence of a cAMP-responsive element in the 5-untranslated region of the AQP2 gene (92, 156) and with the recent demonstration that mice with inherently low cAMP levels have low expression of AQP2 (DI +/+). There was a very slow recovery in AQP2 expression and restoration of urinary concentration after cessation of lithium treatment (149) consistent with clinical findings. However, treatment of lithium-diuretic rats with high doses of the specific V2-receptor agonist dDAVP was able to cause efficient delivery of AQP2 to the apical plasma membrane (a greater fraction of total AQP2 was found in the membrane than seen in control animals), but there was only a modest increase in AQP2 expression relative to animals treated with lithium alone. On the contrary, thirsting of the rats for 2 days resulted in a much larger increase in AQP2 protein levels, but little targeting to the apical plasma membrane (a lot of AQP2 was found in intracellular domains, i.e., intracellular vesicles). Consequently, this study showed that thirsting was a more potent stimulus for AQP2 expression than dDAVP administration in the present model and provided evidence for the presence of a vasopressin-independent regulation of AQP2 expression levels. The existence of such a signal transduction pathway has recently gained support (58). Similar to the slow recovery of urinary concentration inability seen in patients who have been on lithium treatment, lithium-treated rats also showed a slow recovery. The suppression of AQP2 levels was parallelled by a persistent urinary concentrating defect after removal of lithium from the diet (149).
2. Electrolyte disturbances associated with NDI
It is known that both hypokalemia and hypercalcemia, clinically important electrolyte abnormalities, are associated with polyuria due to a vasopressin-resistant urinary concentrating defect. However, recently, at least part of the underlying molecular defects involved in the development of this polyuria was described. With the use of well-established rat models to study these abnormalities, it has recently been shown that both hypokalemia and hypercalcemia are associated with a significant downregulation of AQP2 expression (54, 150, 208).
Treating rats on a potassium-deficient diet for 11 days resulted in downregulation of AQP2 expression in both inner medulla and cortex (27 ± 3 and 34 ± 15% of control levels, respectively). Thus hypokalemia is associated with significantly less downregulation of AQP2 compared with that seen in lithium-treated rats. In parallel with the less extensive AQP2 downregulation, urine production increased moderately from 11 ± 1 to 30 ± 4 ml/day, i.e., much less increase in urine output compared with lithium-treated animals. The increase in urine output was associated with an impaired urine-concentrating ability. In response to 12-h water deprivation, urine osmolality was significantly lower in hypokalemic rats compared with controls. Treating rats with a normal potassium containing diet for 7 days after an 11-day period on a potassium-deficient diet showed normal urinary concentrating capacity and normalization of AQP2 levels. Taken together, the results support the view that there is a causative link between the inability to concentrate urine and the reduced AQP2 levels.
Another electrolyte disturbance, hypercalcemia, is also frequently associated with a urinary concentrating defect and polyuria. An experimental model of vitamin D-induced hypercalcemia in rats has been used by two groups to investigate if dysregulation of AQP2 may also participate in this condition (54, 208). The molecular mechanisms resulting in vasopressin resistance in hypercalcemic conditions remain incompletely understood. Rats treated orally for 7 days with dihydrotachysterol produced a significant hypercalcemia with a 15 ± 2% increase in plasma calcium concentration compared with controls. Hypercalcemic rats demonstrated a threefold increase in urine production, whereas urine osmolality decreased from 2,007 to 925 mosmol/kgH2O. Consistent with this, immunoblotting and densitometry of membrane fractions revealed a 50% reduction in AQP2 expression in kidney inner medulla from hypercalcemic