Genetic Models of Diabetes Insipidus

Valtin, Heinz

doi:10.1002/cphy.cp080228

Cited by 20 publications

(13 citation statements)

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“…These mice have high levels of rolipram-sensitive cAMPphosphodiesterase type IV activity and low cytosolic cAMP levels and are unable to raise the cytosolic cAMP in response to vasopressin (33). They have extensive polyuria and low urine osmolality (4,16).…”

Section: Discussionmentioning

confidence: 99%

Aldose reductase deficient mice develop nephrogenic diabetes insipidus

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Aldose reductase (ALR2) is thought to be involved in the pathogenesis of various diseases associated with diabetes mellitus, such as cataract, retinopathy, neuropathy, and nephropathy. However, its physiological functions are not well understood. We developed mice deficient in this enzyme and found that they had no apparent developmental or reproductive abnormality except that they drank and urinated significantly more than their wild-type littermates. These ALR2-deficient mice exhibited a partially defective urine-concentrating ability, having a phenotype resembling that of nephrogenic diabetes insipidus.Aldose reductase (ALR2) is the first enzyme in the polyol pathway. It was first described by Hers in 1956 (13). Using NADPH as a cofactor, it reduces glucose to sorbitol in addition to reducing other sugars to their respective polyols. The activation of the sorbitol pathway under hyperglycemic conditions is thought to be the cause of diabetic lesions in tissues where the import of glucose is independent of insulin, such as the lens, vascular cells, and nervous tissues (18,28). Although ALR2 has been thoroughly studied for its role in the etiology of diabetic complications, its physiological functions are not well understood. ALR2 is present in most tissues surveyed and has been implicated in a wide variety of physiological functions. It is thought to be responsible for synthesizing fructose in the seminal vesicle to be used as the main energy source for sperm motility, because fructose is converted from sorbitol by the enzyme sorbitol dehydrogenase (SORD) (13). ALR2 can efficiently reduce methyglyoxal (35), 4-hydroxynonenal (34), and 3-deoxyglucosone (29), suggesting that it may be responsible for detoxification of these and other harmful metabolites. Another postulated function of ALR2 is osmoprotection in the kidney (1). This is based on the facts that sorbitol is an inert compound ideally suited as an osmolyte and that its intracellular concentration in certain tissues can reach a high enough level to affect osmotic pressure. Further, elevated extracellular NaCl was shown to elicit a marked increase in ALR2 expression and the accumulation of intracellular sorbitol in the cell line cultured from rabbit renal medullae (1), suggesting that kidney cells respond to an increase in extracellular osmotic pressure by producing more sorbitol. In support of this notion, osmotic response elements have been identified in the promoter regions of the rabbit (10) and human (20) ALR2 genes.To test these proposed functions of ALR2, we developed two mouse lines deficient in this enzyme. ALR2 knockout mice (Aldor1 Ϫ/Ϫ ) appeared to grow normally and did not show any obvious abnormalities in their reproductive function. Upon closer examination, they were found to have developed polyuria and polydipsia. These Aldor1 Ϫ/Ϫ mice exhibit a partially defective urine-concentrating ability, leading to a phenotype resembling that of diabetes insipidus (DI).There are several known causes of DI. Deficiency in the synthesis or secretion of t...

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Section: Discussionmentioning

confidence: 99%

Aldose reductase deficient mice develop nephrogenic diabetes insipidus

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“…Furthermore, the functional status of TIDA neurons can be readily monitored in the rats by measuring circulating PRL levels. The advantages of the neuroendocrine system for the evaluation of gene therapy strategies in the CNS has already been demonstrated in the Brattleboro rat, a mutant lacking arginine-vasopressin (AVP) which is used as a model of diabetes insipidus (Valtin, 1992). When an adenoviral vector encoding the rat AVP cDNA was stereotaxically injected into the supraoptic nucleus of Brattleboro rats, a substantial expression of AVP in magnocellular cells as well as the presence of immunohistochemically detectable AVP in their axons projecting to the posterior pituitary were detected .…”

Section: -Discussionmentioning

confidence: 99%

Glial cell line-derived neurotrophic factor gene therapy ameliorates chronic hyperprolactinemia in senile rats

et al. 2010

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Progressive dysfunction of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons during normal aging is associated in the female rat with chronic hyperprolactinemia. We assessed the effectiveness of glial cell line-derived neurotrophic factor (GDNF) gene therapy to restore TIDA neuron function in senile female rats and reverse their chronic hyperprolactinemia. Young (2.5 months) and senile (29 months) rats received a bilateral intrahypothalamic injection (10 10 pfu) of either an adenoviral vector expressing the gene for β-galactosidase; (Y-βgal and S-βgal, respectively) or a vector expressing rat GDNF (Y-GDNF and S-GDNF, respectively). Transgenic GDNF levels in supernatants of GDNF adenovector-transduced N2a neuronal cell cultures were 25 ± 4 ng/ml, as determined by bioassay. In the rats, serum prolactin (PRL) was measured at regular intervals. On day 17 animals were sacrificed and neuronal nuclear antigen (NeuN) and tyrosine hydroxylase (TH) immunoreactive cells counted in the arcuate-periventricular hypothalamic region. The S-GDNF but not the S-βgal rats, showed a significant reduction in body weight. The chronic hyperprolactinemia of the senile females was significantly ameliorated in the S-GDNF rats (p< 0.05) but not in the Sβgal rats. Neither age nor GDNF induced significant changes in the number of NeuN and TH neurons. We conclude that transgenic GDNF ameliorates chronic hyperprolactinemia in aging female rats, probably by restoring TIDA neuron function. Keywordsaging; DA neurodegeneration; TIDA neurons; chronic hyperprolactinemia; GDNF; gene therapyThe dopaminergic (DA) neurons of the rat hypothalamus are grouped into two main areas, A 12 and A 14, (Dahlstrom and Fuxe, 1964;Tillet and Kitahama, 1998) with the DA perikarya of the A 12 area being located in the arcuate (ARC) nucleus and in the periarcuate region (Kawano and Daikoku, 1997). The A 14 DA neurons are mainly located within the paraventricular (PaV) and periventricular (PeV) nuclei, with a few scattered DA neurons in Goudreau et al., 1992). The A 12 area and its corresponding axon terminals constitute the tuberoinfundibular (TIDA) system, whereas the A 14 area and its fibers are known as the periventricular dopaminergic system. Both systems regulate prolactin (PRL) secretion by exerting a tonic inhibitory control on both PRL secretion and lactotroph proliferation (BenJonathan et al., 1989).In female rats, aging brings about a progressive dysfunction and loss of TIDA neurons. Degeneration and loss of TIDA neurons during normal aging is associated, in the female rat, with a progressive hyperprolactinemia (Goya et al., 1990) and the development of pituitary prolactinomas (Console et al., 1997). This neuroendocrine pathology provides a unique animal model to assess the efficacy of therapeutic strategies aimed at protecting central DA neurons. Interestingly, Parkinsonian patients were reported to show functional alterations in the hypothalamo-PRL axis (Cusimano et al., 1991).Glial cell line-derived neurotrophic factor (GDNF), a distant ...

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“…This result underlines the crucial role of PDFA activity. This isoform seems to be hyperactive in DI +/+ mice suffering from NDI (Valtin 1992; see 6). The result also suggests that about half of the phosphodiesterase activity has to be accounted for by other phosphodiesterases, of which PDE1, 3 and 5 seem to be present in the rat inner medullary collecting duct (Yamaki et al 1992; for review see: Dousa 1999).…”

Section: Cyclic Amp-triggered Exocytotic Insertion Of Aqp2 Into Apicamentioning

confidence: 99%

“…The Brattleboro rat, a model for central diabetes insipidus, has already been introduced (see 3). The DI +/+ mouse is a model or NDI (see 4.1; Valtin 1992). In the latter case, the disease is caused by an abnormally high activity of cAMP phosphodiesterase type 4 (PDE4), and NDI is successfully treated with the PDE4 inhibitor rolipram.…”

Section: Model Systems To Study the Short And Long Term Regulation Ofmentioning

confidence: 99%