Congenital nephrogenic diabetes insipidus: the current state of affairs

Wesche, Daniel; Deen, Peter M.T.; Knoers, Nine V A M

doi:10.1007/s00467-012-2118-8

Cited by 105 publications

(131 citation statements)

References 161 publications

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“…We could not detect mutations in the two genes in seven families (9 %, congenital NDI patients [4]. Possibilities such as the presence of mutations in the promoter regions of the AVPR2 or AQP2 genes are a likely explanation [4].…”

Section: Aqp2 Mutations Causing Ndimentioning

confidence: 73%

“…Possibilities such as the presence of mutations in the promoter regions of the AVPR2 or AQP2 genes are a likely explanation [4]. Our mutational analysis does not usually cover the promoter regions; thus, this possibility remains to be examined.…”

Section: Aqp2 Mutations Causing Ndimentioning

confidence: 99%

“…Therefore, NDI patients manifest polyuria and polydipsia. The hereditary (congenital) form of NDI is relatively rare, and is known to be caused by mutations in two genes, the arginine vasopressin type 2 receptor (AVPR2) and the water channel aquaporin 2 (AQP2) [1][2][3][4]. These two genes encode two membrane proteins that are oppositely located at the basolateral and apical membranes of the collecting duct principal cells, respectively, and constitute the fundamental components of urine concentrating machinery [5,6].…”

Section: Introductionmentioning

confidence: 99%

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Hereditary nephrogenic diabetes insipidus in Japanese patients: analysis of 78 families and report of 22 new mutations in AVPR2 and AQP2

et al. 2012

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Background Familial form of nephrogenic diabetes insipidus (NDI) is a rare hereditary disease caused by arginine vasopressin type 2 receptor (AVPR2) or water channel aquaporin 2 (AQP2) gene mutations. It is speculated that 90 % of NDI families carry disease-causing mutations in AVPR2 and 10 % carry the mutations in AQP2; however, these percentages have not been supported by actual data. It is also unknown whether these percentages vary in different ethnic groups. Methods Gene mutation analyses were performed for 78 Japanese NDI families. All exons and intron-exon boundaries of the AVPR2 and AQP2 genes were directly sequenced. Results A total of 62 families (79 %) carried diseasecausing mutations in AVPR2, while nine families (12 %) carried mutations in AQP2. We identified 22 novel putatively disease-causing mutations (19 in AVPR2 and 3 in AQP2). Regarding AVPR2, 52 disease-causing mutations were identified. Among them, missense mutations were most common (54 %), followed by deletion mutations. In the 64 women who had monoallelic disease-causing AVPR2 mutations, 16 (25 %) had NDI symptoms, including 4 complete NDI subjects. Regarding AQP2, 9 disease-causing mutations were identified in nine families. Two missense mutations and one deletion mutation showed a recessive inheritance, while one missense mutation and five small deletion mutations in the C-terminus of AQP2 showed a dominant inheritance.Conclusions Most Japanese NDI families carry diseasecausing mutations in AVPR2 and 12 % carry mutations in AQP2. A total of 22 novel putatively disease-causing mutations were identified. The relatively high occurrence of symptomatic carriers of AVPR2 mutations needs attention.

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Section: Aqp2 Mutations Causing Ndimentioning

confidence: 73%

Section: Aqp2 Mutations Causing Ndimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hereditary nephrogenic diabetes insipidus in Japanese patients: analysis of 78 families and report of 22 new mutations in AVPR2 and AQP2

et al. 2012

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“…Nephrogenic diabetes insipidus (NDI) is commonly caused by mutations of the vasopressin 2 receptor (V2R) gene; a specific therapy for this disease is lacking (30,31). We explored the therapeutic potential of sPRR-His in a mouse model of NDI induced with a V2R antagonist, OPC.…”

Section: Therapeutic Potential Of Sprr-his For Treatment Of Nephrogenicmentioning

confidence: 99%

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

135

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The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent β-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.soluble (pro)renin receptor | liver X receptor | aquaporin-2 | frizzled-8 | β-catenin F ull-length (Pro)renin receptor (PRR), a 350-amino acid transmembrane receptor for prorenin and renin, is subjected to protease-mediated cleavage to produce a 28-kDa protein of the N-terminal extracellular domain, the soluble (pro)renin receptor (sPRR), and the 8.9-kDa C-terminal intracellular domain called "M8.9" (1, 2). Before the cloning of full-length PRR in mesangial cells as an integral 39-kDa membrane protein (3), M8.9 was identified as a truncated protein associated with the vacuolar H + -ATPase (V-ATPase) from bovine chromatin granules (4). The cleavage occurs in Golgi apparatus through furin (5) or ADMA19 (6). An sPRR ELISA kit has been developed to detect sPRR in plasma and urine samples (7) . With this assay, increased serum sPRR levels have been demonstrated in patients with heart failure (8), kidney disease (9, 10), hypertension (11), and preeclampsia (2). Moreover, serum sPRR is positively associated with serum creatinine, blood urea nitrogen, and urine protein and is inversely associated with the estimated glomerular filtration rate in patients with chronic kidney disease caused by hypertension...

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“…1,2 The role of the antidiuretic hormone vasopressin and its receptor, V2R, in the signaling cascade that leads to membrane accumulation of AQP2 in collecting-duct principal cells, and to an increase in renal water reabsorption, is well established. 3 The involvement of VP-induced cAMP elevation by adenylyl cyclase activation, and subsequent protein kinase A-induced phosphorylation of AQP2, is also well known.…”

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confidence: 99%

Aquaporin-2 Inhibitors

Brown

2013

Journal of the American Society of Nephrology

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The critical contribution of aquaporin-2 (AQP) to water homeostasis in mammals is highlighted by the severe concentrating defects seen in humans with mutations in the AQP2 gene and in mice that are AQP2 null or have loss-of-function mutations in AQP2. 1,2 The role of the antidiuretic hormone vasopressin and its receptor, V2R, in the signaling cascade that leads to membrane accumulation of AQP2 in collecting-duct principal cells, and to an increase in renal water reabsorption, is well established. 3 The involvement of VP-induced cAMP elevation by adenylyl cyclase activation, and subsequent protein kinase A-induced phosphorylation of AQP2, is also well known. Defects in any of the major components of this signaling cascade have the potential to lead to aberrant AQP2 trafficking and function, with an associated loss of urine-concentrating ability or an inappropriate increase in collecting-duct water retention.Decreased water reabsorption leads to diabetes insipidus, either central (loss of vasopressin) or nephrogenic (loss of V2R or AQP2 function). Excessive AQP2 expression and plasma membrane localization are associated with such conditions as congestive heart failure, cirrhosis of the liver, and the syndrome of inappropriate antidiuretic hormone secretion. In such cases, inappropriate water re-absorption can lead to moderate or severe hyponatremia and its subsequent complications, sometimes fatal. Furthermore, many defects in water homeostasis result from acquired conditions, such as lithium-induced nephrogenic diabetes insipidus, a common consequence of the use of this compound as therapy for bipolar disorder.Considerable effort has therefore been expended over the past several years to identify components of the AQP2 trafficking pathway that could be targeted by drugs or other therapeutic strategies in order to alleviate the consequences of these diseases. On the basis of current knowledge of the signaling and trafficking pathways that have been elucidated by several groups, different strategies have been explored. These include bypassing the V2R-mediated signaling pathway using alternative cyclic nucleotide-generating agents, such as the cyclic guanosine monophopshate phosphodiesterase inhibitor sildenafil; 4,5 activating alternative pathways, including prostaglandin signaling; 6 and modulating trafficking with drugs, including statins, that affect the actin cytoskeleton, 7,8 a key factor in endo-and exocytotic events, as well as inhibiting endocytosis directly. 9 Some of these interventions indeed result in increased membrane AQP2 expression, and they increase urinary-concentrating ability in animal models, including vasopressin-deficient Brattleboro rats and lithium-treated rats. 2 In the current issue of JASN, Bogum et al. 10 use a smallmolecule screening approach to identify chemical compounds that inhibit cAMP-induced AQP2 membrane accumulation. Such compounds would function as aquaretics and counteract the effects of elevated vasopressin/cAMP or increased AQP2 levels in conditions that might lead to exce...

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Congenital nephrogenic diabetes insipidus: the current state of affairs

Cited by 105 publications

References 161 publications

Hereditary nephrogenic diabetes insipidus in Japanese patients: analysis of 78 families and report of 22 new mutations in AVPR2 and AQP2

Hereditary nephrogenic diabetes insipidus in Japanese patients: analysis of 78 families and report of 22 new mutations in AVPR2 and AQP2

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

Aquaporin-2 Inhibitors

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