The collecting ducts of some individuals do not respond normally to AVP. These individuals cannot maximally concentrate their urine and consequently have polyuria and polydipsia. This clinical entity is termed nephrogenic diabetes insipidus to distinguish it from central diabetes insipidus. Nephrogenic diabetes insipidus can result from a number of systemic disorders and more rarely occurs as a result of inherited disorders. Many of the acquired forms of nephrogenic diabetes insipidus are the result of decreased expression of AQP2 in the collecting duct. Decreased expression of AQP2 has been documented in the urine concentrating defects associated with hypokalemia, lithium ingestion (35% of individuals who take lithium for bipolar disorder develop some degree of nephrogenic diabetes insipidus), ureteral obstruction, low-protein diet, and hypercalcemia. The inherited forms of nephrogenic diabetes insipidus reflect mutations in the AVP receptor (V2 receptor) gene or the AQP2 gene. Approximately 90% of hereditary forms of nephrogenic diabetes insipidus are the result of mutations in the V2 receptor gene, with the other 10% the result of mutations in the AQP2 gene. Since the gene for the V2 receptor is located on the X chromosome, these inherited forms of nephrogenic diabetes insipidus are X-linked. The gene coding for AQP2 is located on chromosome 12 and is inherited as both an autosomal recessive as well as an autosomal dominant defect. As noted in , aquaporins exist as homotetramers. This homotetramer formation explains the difference between the two forms of AQP2-related nephrogenic diabetes insipidus. In the recessive form, heterozygotes produce both normal AQP2 and defective AQP2 molecules. The defective AQP2 monomer is retained in the endoplasmic reticulum of the cell, and thus the homotetramers that do form only contain normal molecules. Thus mutations in both alleles are required to produce nephrogenic diabetes insipidus. In the autosomal dominant form, the defective monomers can form tetramers with normal monomers as well as defective monomers. However, tetramers containing defective monomers are unable to traffic to the apical membrane.
Recently, individuals have been found that have activating (gain-of-function) mutations in the V2 receptor gene. Thus the receptor is constitutively activated even in the absence of AVP. These individuals have laboratory findings similar to those seen in SIADH, including reduced plasma osmolality, hyponatremia (reduced plasma [Na+]), and urine more concentrated than would be expected from the reduced body fluid osmolality. However, unlike SIADH where circulating levels of AVP are elevated and thus responsible for water retention by the kidneys, these individuals have undetectable levels of AVP in their plasma. This new clinical entity has been termed nephrogenic syndrome of inappropriate antidiuresis.
AVP secretion, only occurs in response to effective osmoles (e.g., NaCl). Even less is known about the pathways involved in the thirst response to decreased blood volume or pressure, but it is believed that the pathways are the same as those involved in the volume and pressure-related regulation of AVP secretion. Angiotensin II acting on cells of the thirst center also evokes the sensation of thirst. Because angiotensin II levels are increased when blood volume and pressure are reduced, this effect of angiotensin II contributes to the homeostatic response that restores and maintains body fluids at their normal volume.