Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus

2015 ◽  
Vol 42 (1) ◽  
pp. 65-69 ◽  
Author(s):  
Farahnak Assadi ◽  
Fatemeh Ghane Sharbaf
Keyword(s):  
Diabetes Insipidus ◽  
Conventional Therapy ◽  
Nephrogenic Diabetes Insipidus ◽  
Collecting Duct ◽  
Water Channel ◽  
Substantial Reduction ◽  
Experimental Studies ◽  
Urine Volume ◽  
Phosphodiesterase Inhibitor ◽  
Congenital Nephrogenic Diabetes Insipidus

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.

Hydrochlorothiazide attenuates lithium-induced nephrogenic diabetes insipidus independently of the sodium-chloride cotransporter

2014 ◽  
Vol 306 (5) ◽  
pp. F525-F533 ◽  
Author(s):  
Anne P. Sinke ◽  
Marleen L. A. Kortenoeven ◽  
Theun de Groot ◽  
Ruben Baumgarten ◽  
Olivier Devuyst ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Knockout Mice ◽  
Nephrogenic Diabetes Insipidus ◽  
Collecting Duct ◽  
Water Channel ◽  
Urine Volume ◽  
Tubuloglomerular Feedback ◽  
Independent Effect ◽  
Cortical Collecting Duct

Lithium is the most common cause of nephrogenic diabetes insipidus (Li-NDI). Hydrochlorothiazide (HCTZ) combined with amiloride is the mainstay treatment in Li-NDI. The paradoxical antidiuretic action of HCTZ in Li-NDI is generally attributed to increased sodium and water uptake in proximal tubules as a compensation for increased volume loss due to HCTZ inhibition of the Na-Cl cotransporter (NCC), but alternative actions for HCTZ have been suggested. Here, we investigated whether HCTZ exerted an NCC-independent effect in Li-NDI. In polarized mouse cortical collecting duct (mpkCCD) cells, HCTZ treatment attenuated the Li-induced downregulation of aquaporin-2 (AQP2) water channel abundance. In these cells, amiloride reduces cellular Li influx through the epithelial sodium channel (ENaC). HCTZ also reduced Li influx, but to a lower extent. HCTZ increased AQP2 abundance on top of that of amiloride and did not affect the ENaC-mediated transcellular voltage. MpkCCD cells did not express NCC mRNA or protein. These data indicated that in mpkCCD cells, HCTZ attenuated lithium-induced downregulation of AQP2 independently of NCC and ENaC. Treatment of Li-NDI NCC knockout mice with HCTZ revealed a significantly reduced urine volume, unchanged urine osmolality, and increased cortical AQP2 abundance compared with Li-treated NCC knockout mice. HCTZ treatment further resulted in reduced blood Li levels, creatinine clearance, and alkalinized urinary pH. Our in vitro and in vivo data indicate that part of the antidiuretic effect of HCTZ in Li-NDI is NCC independent and may involve a tubuloglomerular feedback response-mediated reduction in glomerular filtration rate due to proximal tubular carbonic anhydrase inhibition.

scholarly journals Congenital nephrogenic diabetes insipidus accompanied with central nephrogenic diabetes secondary to pituitary surgery -a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Zhang ◽  
Yimin Shen ◽  
Yuezhong Ren ◽  
Yvbo Xin ◽  
Lijun Wang
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Direct Detection ◽  
Urine Volume ◽  
Pituitary Surgery ◽  
Accurate Method ◽  
Heterozygous Mutation ◽  
Case Presentation ◽  
Congenital Nephrogenic Diabetes Insipidus

Abstract Background Diabetes insipidus (DI) can be a common cause of polydipsia and polyuria. Here, we present a case of congenital nephrogenic diabetes insipidus (CNDI) accompanied with central diabetes insipidus (CDI) secondary to pituitary surgery. Case presentation A 24-year-old Chinese woman came to our hospital with the complaints of polydipsia and polyuria for 6 months. Six months ago, she was detected with pituitary apoplexy, and thereby getting pituitary surgery. However, the water deprivation test demonstrated no significant changes in urine volume and urine gravity in response to fluid depression or AVP administration. In addition, the genetic results confirmed a heterozygous mutation in arginine vasopressin receptor type 2 (AVPR2) genes. Conclusions She was considered with CNDI as well as acquired CDI secondary to pituitary surgery. She was given with hydrochlorothiazide (HCTZ) 25 mg twice a day as well as desmopressin (DDAVP, Minirin) 0.1 mg three times a day. There is no recurrence of polyuria or polydipsia observed for more than 6 months. It can be hard to consider AVPR2 mutation in female carriers, especially in those with subtle clinical presentation. Hence, direct detection of DNA sequencing with AVPR2 is a convenient and accurate method in CNDI diagnosis.

scholarly journals Novel Treatment for Lithium-Induced Nephrogenic Diabetes Insipidus Rat Model Using the Sendai-Virus Vector Carrying Aquaporin 2 Gene

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5803-5810 ◽  
Author(s):  
Hidetaka Suga ◽  
Hiroshi Nagasaki ◽  
Taka-aki Kondo ◽  
Yoshiki Okajima ◽  
Chizuko Suzuki ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Sendai Virus ◽  
Collecting Duct ◽  
Water Channel ◽  
Vector System ◽  
Aquaporin 2 ◽  
Chronic Disorder ◽  
Life Threatening ◽  
Aqp2 Gene

Congenital nephrogenic diabetes insipidus (NDI) is a chronic disorder involving polyuria and polydipsia that results from unresponsiveness of the renal collecting ducts to the antidiuretic hormone vasopressin. Either of the genetic defects in vasopressin V2 receptor or the water channel aquaporin 2 (AQP2) cause the disease, which interfere the water reabsorption at the epithelium of the collecting duct. An unconscious state including a perioperative situation can be life threatening because of the difficulty to regulate their water balance. The Sendai virus (SeV) vector system deleting fusion protein (F) gene (SeV/ΔF) is considered most suitable because of the short replication cycle and nontransmissible character. An animal model for NDI with reduced AQP2 by lithium chloride was used to develop the therapy. When the SeV/ΔF vector carrying a human AQP2 gene (AQP2-SeV/ΔF) was administered retrogradely via ureter to renal pelvis, AQP2 was expressed in the renal collecting duct to reduce urine output and water intake by up to 40%. In combination with the retorograde administration to pelvis, this system could be the cornerstone for the applicable therapies on not only NDI patients but also other diseases associate with the medullary collecting duct.

scholarly journals AQP2: Mutations Associated with Congenital Nephrogenic Diabetes Insipidus and Regulation by Post-Translational Modifications and Protein-Protein Interactions

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2172
Author(s):  
Chao Gao ◽  
Paul J. Higgins ◽  
Wenzheng Zhang
Keyword(s):  
Diabetes Insipidus ◽  
Protein Interactions ◽  
Nephrogenic Diabetes Insipidus ◽  
Molecular Mechanisms ◽  
Collecting Duct ◽  
Principal Cell ◽  
Apical Plasma Membrane ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Congenital Nephrogenic Diabetes Insipidus

As a rare hereditary disease, congenital nephrogenic diabetes insipidus (NDI) is clinically characterized by polyuria with hyposthenuria and polydipsia. NDI results from collecting duct principal cell hyporesponsiveness or insensitivity to the antidiuretic action of arginine vasopressin (AVP). The principal cell-specific water channel aquaporin-2 (AQP2) plays an essential role in water reabsorption along osmotic gradients. The capacity to accumulate AQP2 in the apical plasma membrane in response to decreased fluid volume or increased plasma osmolality is critically regulated by the antidiuretic hormone AVP and its receptor 2 (AVPR2). Mutations in AVPR2 result in X-linked recessive NDI, the most common form of inherited NDI. Genetic defects in AQP2 cause autosomal recessive or dominant NDI. In this review, we provide an updated overview of the genetic and molecular mechanisms of congenital NDI, with a focus on the potential disease-causing mutations in AVPR2 and AQP2, the molecular defects in the AVPR2 and AQP2 mutants, post-translational modifications (i.e., phosphorylation, ubiquitination, and glycosylation) and various protein-protein interactions that regulate phosphorylation, ubiquitination, tetramerization, trafficking, stability, and degradation of AQP2.

scholarly journals Activation of AQP2 water channels by protein kinase A: therapeutic strategies for congenital nephrogenic diabetes insipidus

2021 ◽  
Author(s):  
Fumiaki Ando
Keyword(s):  
Protein Kinase ◽  
Diabetes Insipidus ◽  
Protein Kinase A ◽  
Nephrogenic Diabetes Insipidus ◽  
Water Channel ◽  
Adenosine Monophosphate ◽  
Loss Of Function ◽  
Collecting Ducts ◽  
Congenital Nephrogenic Diabetes Insipidus ◽  
Kinase A

Abstract Background Congenital nephrogenic diabetes insipidus (NDI) is primarily caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R). Renal unresponsiveness to the antidiuretic hormone vasopressin impairs aquaporin-2 (AQP2) water channel activity and water reabsorption from urine, resulting in polyuria. Currently available symptomatic treatments inadequately reduce patients’ excessive amounts of urine excretion, threatening their quality of life. In the past 25 years, vasopressin/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) has been believed to be the most important signaling pathway for AQP2 activation. Although cAMP production without vasopressin is the reasonable therapeutic strategy for congenital NDI caused by V2R mutations, the efficacy of candidate drugs on AQP2 activation is far less than that of vasopressin. Results Intracellular distribution and activity of PKA are largely controlled by its scaffold proteins, A-kinase anchoring proteins (AKAPs). Dissociating the binding of AKAPs and PKA significantly increased PKA activity in the renal collecting ducts and activated AQP2 phosphorylation and trafficking. Remarkably, the AKAPs–PKA disruptor FMP-API-1 increased transcellular water permeability in isolated renal collecting ducts to the same extent as vasopressin. Moreover, derivatives of FMP-API-1 possessed much more high potency. FMP-API-1/27 is the first low-molecular-weight compound to be discovered that can phosphorylate AQP2 more effectively than preexisting drug candidates. Conclusion AKAP-PKA disruptors are a promising therapeutic target for congenital NDI. In this article, we shall discuss the pathophysiological roles of PKA and novel strategies to activate PKA in renal collecting ducts.

Inherited secondary nephrogenic diabetes insipidus: concentrating on humans

2013 ◽  
Vol 304 (8) ◽  
pp. F1037-F1042 ◽  
Author(s):  
D. Bockenhauer ◽  
D. G. Bichet
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Collecting Duct ◽  
Lithium Treatment ◽  
Water Channel ◽  
Underlying Mechanism ◽  
Bartter Syndrome ◽  
Experimental Models ◽  
Urinary Concentration ◽  
Apparent Mineralocorticoid Excess

The study of human physiology is paramount to understanding disease and developing rational and targeted treatments. Conversely, the study of human disease can teach us a lot about physiology. Investigations into primary inherited nephrogenic diabetes insipidus (NDI) have contributed enormously to our understanding of the mechanisms of urinary concentration and identified the vasopressin receptor AVPR2, as well as the water channel aquaporin-2 (AQP2), as key players in water reabsorption in the collecting duct. Yet, there are also secondary forms of NDI, for instance as a complication of lithium treatment. The focus of this review is secondary NDI associated with inherited human diseases, such as Bartter syndrome or apparent mineralocorticoid excess. Currently, the underlying pathophysiology of this inherited secondary NDI is unclear, but there appears to be true AQP2 deficiency. To better understand the underlying mechanism(s), collaboration between clinical and experimental physiologists is essential to further investigate these observations in appropriate experimental models.

scholarly journals Nephrogenic diabetes insipidus in mice caused by deleting COOH-terminal tail of aquaporin-2

2007 ◽  
Vol 292 (5) ◽  
pp. F1334-F1344 ◽  
Author(s):  
Peijun P. Shi ◽  
Xiao R. Cao ◽  
Jing Qu ◽  
Ken A. Volk ◽  
Patricia Kirby ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Hormonal Regulation ◽  
Nephrogenic Diabetes Insipidus ◽  
Mdck Cells ◽  
Collecting Duct ◽  
Phosphorylation Site ◽  
Water Channel ◽  
Urine Osmolality ◽  
Functional Expression ◽  
Aquaporin 2

In mammals, the hormonal regulation of water homeostasis is mediated by the aquaporin-2 water channel (Aqp2) of the collecting duct (CD). Vasopressin induces redistribution of Aqp2 from intracellular vesicles to the apical membrane of CD principal cells, accompanied by increased water permeability. Mutations of AQP2 gene in humans cause both recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. In this study, we generated a line of mice with the distal COOH-terminal tail of the Aqp2 deleted ( Aqp2Δ 230), including the protein kinase A phosphorylation site (S256), but still retaining the putative apical localization signal (221–229) at the COOH-terminal. Mice heterozygous for the truncation appear normal. Homozygotes are viable to adulthood, with reduced urine concentrating capacity, increased urine output, decreased urine osmolality, and increased daily water consumption. Desmopressin increased urine osmolality in wild-type mice but had no effect on Aqp2Δ 230/Δ 230 mice. Kidneys from affected mice showed CD and pelvis dilatation and papillary atrophy. By immunohistochemical and immunoblot analyses using antibody against the NH2-terminal region of the protein Aqp2Δ 230/Δ 230 mice had a markedly reduced protein abundance. Expression of the truncated protein in MDCK cells was consistent with a small amount of functional expression but no stimulation. Thus we have generated a mouse model of NDI that may be useful in studying the physiology and potential therapy of this disease.

scholarly journals Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus

2006 ◽  
Vol 291 (2) ◽  
pp. F257-F270 ◽  
Author(s):  
Joris H. Robben ◽  
Nine V. A. M. Knoers ◽  
Peter M. T. Deen
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Current Knowledge ◽  
Collecting Duct ◽  
Water Channel ◽  
Water Reabsorption ◽  
Aquaporin 2 ◽  
Electrolyte Disturbances ◽  
Genes Encoding ◽  
V2 Receptor

In the renal collecting duct, water reabsorption is regulated by the antidiuretic hormone vasopressin (AVP). Binding of this hormone to the vasopressin V2 receptor (V2R) leads to insertion of aquaporin-2 (AQP2) water channels in the apical membrane, thereby allowing water reabsorption from the pro-urine to the interstitium. The disorder nephrogenic diabetes insipidus (NDI) is characterized by the kidney's inability to concentrate pro-urine in response to AVP, which is mostly acquired due to electrolyte disturbances or lithium therapy. Alternatively, NDI is inherited in an X-linked or autosomal fashion due to mutations in the genes encoding V2R or AQP2, respectively. This review describes the current knowledge of the cell biological causes of NDI and how these defects may explain the patients' phenotypes. Also, the increased understanding of these cellular defects in NDI has opened exciting initiatives in the development of novel therapies for NDI, which are extensively discussed in this review.

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