Mouse models for congenital nephrogenic diabetes insipidus: what can we learn from them?

Deen, Peter M.T.

doi:10.1093/ndt/gfl787

Cited by 10 publications

(7 citation statements)

References 18 publications

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“…The disease can result from mutations in the vasopressin type-2 receptor gene (V2R) or mutations in the aquaporin-2 (AQP2) water channel [1][2][3] . Approximately 90% of congenital NDI cases are associated with V2R mutations (X-linked NDI).…”

Section: Introductionmentioning

confidence: 99%

Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus

Assadi

Sharbaf

2015

Am J Nephrol

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Background: Congenital nephrogenic diabetes insipidus (NDI) is characterized by massive polyuria and polydipsia due to defects in the vasopressin-sensitive signaling system expression of the acuaporin-2 (AQP2) water channel of the kidney collecting duct principal cells. Current conventional treatment regimen including hydration, diuretics and non-steroidal anti-inflammatory drugs can only partially reduce polyuria. Recent experimental studies have suggested that treatment with sildenafil, a selective phosphodiesterase inhibitor, may enhance cyclic guanosine monophosphate (cGMP)-mediated apical trafficking of AQP2 and may be effective in increasing water reabsorption in patients with congenital NDI. Patient and Methods: A 4-year old boy with X-linked NDI resistant to conventional therapy was treated with sildenafil for 10 days after a 2-day washout period between the 2 treatment regimens. Aliquots of the 24-hour urine collections before and after treatment were analyzed for urine volume, osmolality, cGMP and AQP2 determinations. Blood samples were also obtained for sodium and osmolality measurements. The primary endpoint was 24-hour urine volume after 10 days of sildenafil and conventional treatments. Results: Compared to conventional therapy, treatment with sildenafil resulted in substantial reduction in 24-hour urine volume (1,764 vs. 950 ml) and serum sodium (148 vs. 139) mEq/l, and increased urine osmolality (104 vs. 215 mOsm/l), and AQP2 excretion (5 vs. 26 fmol/mg creatinine). The patient tolerated sildenafil well and experienced no adverse effects. Conclusions: Sildenafil citrate should be considered an alternative agent in the treatment of X-linked NDI resistant to conventional therapy.

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Section: Introductionmentioning

confidence: 99%

Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus

Assadi

Sharbaf

2015

Am J Nephrol

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“…Withdrawal of AVP triggers the endocytosis of AQP2-containing vesicles and restores the water-impermeable state of the apical membrane. Impairment of AQP2 trafficking, produced by mutations of either V2R or AQP2 genes, is responsible for a dramatic clinical phenotype known as nephrogenic diabetes insipidus (NDI), a disease whose etiology is renal resistance to AVP and whose clinical hallmark is excretion of large volumes of dilute urine (3,4,13,57).…”

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confidence: 99%

Lovastatin-induced cholesterol depletion affects both apical sorting and endocytosis of aquaporin-2 in renal cells

Procino

Barbieri

Carmosino

et al. 2010

American Journal of Physiology-Renal Physiology

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Vasopressin causes the redistribution of the water channel aquaporin-2 (AQP2) from cytoplasmic storage vesicles to the apical plasma membrane of collecting duct principal cells, leading to urine concentration. The molecular mechanisms regulating the selective apical sorting of AQP2 are only partially uncovered. In this work, we investigate whether AQP2 sorting/trafficking is regulated by its association with membrane rafts. In both MCD4 cells and rat kidney, AQP2 preferentially associated with Lubrol WX-insoluble membranes regardless of its presence in the storage compartment or at the apical membrane. Block-and-release experiments indicate that 1) AQP2 associates with detergent-resistant membranes early in the biosynthetic pathway; 2) strong cholesterol depletion delays the exit of AQP2 from the trans-Golgi network. Interestingly, mild cholesterol depletion promoted a dramatic accumulation of AQP2 at the apical plasma membrane in MCD4 cells in the absence of forskolin stimulation. An internalization assay showed that AQP2 endocytosis was clearly reduced under this experimental condition. Taken together, these data suggest that association with membrane rafts may regulate both AQP2 apical sorting and endocytosis.

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“…Swr mice are reported to have renal deficiency associated with nephrogenic diabetes insipidus (NDI) [14]. NDI occurs as a result of an Avpr2 gene mutation in humans [15] and is most common in male mice because the Avpr2 gene is located on the X chromosome [16]. Another animal model of diabetes insipidus, the Brattleboro rat, is also reported to have reduced vasopressin gene expression levels [17,18].…”

Section: Resultsmentioning

confidence: 99%

Reduced aldehyde dehydrogenase activity and arginine vasopressin receptor 2 expression in the kidneys of male TALLYHO/JngJ mice of prediabetic age

Nakamura

2011

Endocrine

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The TALLYHO/JngJ (TH) mouse is a novel polygenic model of type 2 diabetes and exhibits obesity, hyperglycemia (males), hyperinsulinemia, hyperlipidemia, and enlarged pancreatic islets. Since the kidney is damaged by hyperglycemia in other animal models, the present study aimed to determine the kidney phenotype of TH mice using immunoblot and histological analyses of the kidneys of 6-week-old (prediabetic) and 16-week-old TH mice. Interestingly, even 6-week-old male TH mice showed significant increases in kidney weight, compared to C57BL/B6 (B6) mice. Cuboidal parietal epithelium was observed in the Bowman's capsule in male TH mice at the prediabetic age. Water accumulated inside the kidneys of male TH mice in an age-dependent manner, but not in B6 mice. Since Swr/J mice are reported to develop diabetes insipidus and share 86.8% genotype homology with TH mice, the expression level of arginine vasopressin receptor 2 (AVPR2), a candidate protein for diabetes insipidus, was examined and determined to be significantly reduced in the kidneys of prediabetic male TH mice, compared to B6 mice. Aldehyde dehydrogenase (ALDH) activity in the kidneys of prediabetic male TH mice was significantly lower than that in age-matched male B6 mice, while there were no differences between female TH and B6 mice. These results suggest that the kidney phenotype of prediabetic TH mice occurs only in males, accompanied by a reduction in ALDH activity and AVPR2 expression. The kidney phenotype of male TH mice at a prediabetic age becomes evident before the onset of diabetes.

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Mouse models for congenital nephrogenic diabetes insipidus: what can we learn from them?

Cited by 10 publications

References 18 publications

Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus

Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus

Lovastatin-induced cholesterol depletion affects both apical sorting and endocytosis of aquaporin-2 in renal cells

Reduced aldehyde dehydrogenase activity and arginine vasopressin receptor 2 expression in the kidneys of male TALLYHO/JngJ mice of prediabetic age

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