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1.
Medicine (Baltimore) ; 98(40): e17359, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577731

RESUMO

INTRODUCTION: The clinical and genetic characteristics of nephrogenic diabetes insipidus (NDI) were described via assessing 2 cases of NDI patients from a Chinese family. PATIENT CONCERNS: Two patients who manifest polyuria and polydipsia were admitted to hospital for definite diagnosis. DIAGNOSIS: Water deprivation-vasopressin tests showed that the patients may possess renal-origin diabetes insipidus. All the levels of thyroid-stimulating hormone, luteinizing hormone, follicle stimulation hormone, adrenocorticotropic hormone, prolactin, and growth hormone in both patients were normal. These results were certified that both patients possess a nephropathy-type diabetes insipidus. B-mode ultrasonography and urinalysis test demonstrated that the patient's diabetes insipidus is unlikely to originate from renal organic disease. Remarkably, by nucleotide sequencing, we found a novel mutation c.414_418del in arginine-vasopressin receptor 2 (AVPR2) was related to the disease of NDI. INTERVENTIONS: Two patients were treated with oral hydrochlorothiazide and indomethacin. In addition, low salt diet and potassium supplementation throughout the patients' treatment. OUTCOMES: The clinical symptoms of 2 patients were significantly reduced after targeted therapy. CONCLUSION: A mutation in AVPR2 was discovered to be associated with NID. It provides a new target for molecular diagnosis of NDI, enabling families to undergo genetic counseling and obtain prenatal diagnoses.


Assuntos
Diabetes Insípido Nefrogênico/genética , Receptores de Vasopressinas/genética , Grupo com Ancestrais do Continente Asiático , Diabetes Insípido Nefrogênico/diagnóstico , Diabetes Insípido Nefrogênico/tratamento farmacológico , Humanos , Hidroclorotiazida/uso terapêutico , Indometacina/uso terapêutico
2.
BMJ Case Rep ; 12(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31494590

RESUMO

A 40-year-old Caucasian man developed excessive thirst and polyuria particularly at night over the preceding 6 months. He had been taking lithium for 16 years for the treatment of bipolar affective disorder. Investigations revealed subnormal maximum urinary concentrating ability after 8 hours of water deprivation and only a borderline response of urine osmolality to exogenous desmopressin given by intramuscular injection. A plasma copeptin concentration was elevated at 23 pmol/L. These results were consistent with partial nephrogenic diabetes insipidus. He was encouraged to increase his water intake as dictated by his thirst. In addition, he received amiloride with some improvement in his symptoms. Clinicians should be aware of the risk of nephrogenic diabetes insipidus with long-term lithium use and seek confirmation by a supervised water deprivation test augmented with a baseline plasma copeptin. If increased water intake is insufficient to control symptoms, amiloride may be considered.


Assuntos
Amilorida/uso terapêutico , Antidepressivos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Diabetes Insípido Nefrogênico/tratamento farmacológico , Capacidade de Concentração Renal/efeitos dos fármacos , Lítio/uso terapêutico , Sede/fisiologia , Adulto , Antidepressivos/efeitos adversos , Transtorno Bipolar/fisiopatologia , Diabetes Insípido Nefrogênico/induzido quimicamente , Diabetes Insípido Nefrogênico/fisiopatologia , Humanos , Lítio/efeitos adversos , Masculino , Concentração Osmolar , Poliúria , Resultado do Tratamento , Privação de Água
3.
BMJ Case Rep ; 12(7)2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31352377

RESUMO

Diabetes insipidus is a syndrome characterised by the inability to conserve water or concentrate urine, leading to excessive excretion of urine. In congenital nephrogenic diabetes insipidus (CNDI), common presentations include failure to thrive, polydipsia, polyuria and dehydration. The long trajectory of the disease, coupled with psycho-behavioural changes as a child grows, can precipitate a period of non-adherence despite initial optimal control, especially in the adolescent age group. Social inconvenience of repeated voiding and nocturnal disturbances can lead to adapted urine holding behaviour, also known as non-neurogenic neurogenic bladder (Hinman syndrome). Anatomical changes in the urinary system, such as bladder trabeculation and hydroureteronephrosis, can subsequently give rise to functional renal impairment. We present a case of CNDI with concomitant Hinman syndrome, resulting in acute renal impairment and hypertensive emergency. We aim to raise awareness of the association between these two entities.


Assuntos
Lesão Renal Aguda/etiologia , Comportamento Infantil/psicologia , Diabetes Insípido Nefrogênico/fisiopatologia , Hipertensão/etiologia , Cooperação do Paciente/psicologia , Bexiga Urinaria Neurogênica/etiologia , Lesão Renal Aguda/fisiopatologia , Lesão Renal Aguda/terapia , Criança , Diabetes Insípido Nefrogênico/tratamento farmacológico , Diabetes Insípido Nefrogênico/psicologia , Aconselhamento Diretivo , Humanos , Hipertensão/fisiopatologia , Hipertensão/terapia , Masculino , Índice de Gravidade de Doença , Resultado do Tratamento , Bexiga Urinaria Neurogênica/fisiopatologia
4.
J Am Soc Nephrol ; 30(5): 795-810, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30988011

RESUMO

BACKGROUND: Arginine-vasopressin (AVP) binding to vasopressin V2 receptors promotes redistribution of the water channel aquaporin-2 (AQP2) from intracellular vesicles into the plasma membrane of renal collecting duct principal cells. This pathway fine-tunes renal water reabsorption and urinary concentration, and its perturbation is associated with diabetes insipidus. Previously, we identified the antimycotic drug fluconazole as a potential modulator of AQP2 localization. METHODS: We assessed the influence of fluconazole on AQP2 localization in vitro and in vivo as well as the drug's effects on AQP2 phosphorylation and RhoA (a small GTPase, which under resting conditions, maintains F-actin to block AQP2-bearing vesicles from reaching the plasma membrane). We also tested fluconazole's effects on water flow across epithelia of isolated mouse collecting ducts and on urine output in mice treated with tolvaptan, a VR2 blocker that causes a nephrogenic diabetes insipidus-like excessive loss of hypotonic urine. RESULTS: Fluconazole increased plasma membrane localization of AQP2 in principal cells independent of AVP. It also led to an increased AQP2 abundance associated with alterations in phosphorylation status and ubiquitination as well as inhibition of RhoA. In isolated mouse collecting ducts, fluconazole increased transepithelial water reabsorption. In mice, fluconazole increased collecting duct AQP2 plasma membrane localization and reduced urinary output. Fluconazole also reduced urinary output in tolvaptan-treated mice. CONCLUSIONS: Fluconazole promotes collecting duct AQP2 plasma membrane localization in the absence of AVP. Therefore, it might have utility in treating forms of diabetes insipidus (e.g., X-linked nephrogenic diabetes insipidus) in which the kidney responds inappropriately to AVP.


Assuntos
Aquaporina 2/metabolismo , Transporte Biológico/genética , Colforsina/farmacologia , Diabetes Insípido Nefrogênico/tratamento farmacológico , Fluconazol/farmacologia , Proteína rhoA de Ligação ao GTP/efeitos dos fármacos , Análise de Variância , Animais , Membrana Celular/metabolismo , Células Cultivadas , Diabetes Insípido Nefrogênico/metabolismo , Modelos Animais de Doenças , Túbulos Renais Coletores/citologia , Túbulos Renais Coletores/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fosforilação/genética , Distribuição Aleatória , Transdução de Sinais , Estatísticas não Paramétricas
5.
Adv Protein Chem Struct Biol ; 118: 249-272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31928727

RESUMO

Biased agonists and pharmacological chaperones have demonstrated their potential to harness G protein-coupled receptor signaling and trafficking, and have collectively opened new possibilities in G protein-coupled receptor drug discovery. Combining pharmacological chaperoning and biased agonism properties into a unique given molecule would be of high therapeutic interest in many human diseases resulting from G protein-coupled receptor mutation and misfolding. This strategy perfectly fits to congenital Nephrogenic Diabetes Insipidus which is a typical conformational disease. In most of the cases, it is associated to inactivating mutations of the renal arginine-vasopressin V2 receptor leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone. Cell-permeable pharmacological chaperones have been successfully challenged to restore plasma membrane localization of the receptor mutants and to rescue their function. Interestingly, different classes of pharmacological chaperones of the V2 receptor have proven their usefulness and efficacy, such as antagonists, agonists as well as biased agonists. These compounds, particularly small-molecule biased agonists which elicit the V2-induced Gs protein-dependent signaling pathway, but not V2-related arrestin-dependent cell responses, represent a potential therapeutic treatment of this X-linked genetic pathology.


Assuntos
Diabetes Insípido Nefrogênico/tratamento farmacológico , Dobramento de Proteína , Receptores de Vasopressinas/metabolismo , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Mutação , Receptores de Vasopressinas/agonistas , Receptores de Vasopressinas/genética
6.
Biochem J ; 475(18): 2941-2953, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30068530

RESUMO

A series of compounds formerly identified by high-throughput screening was studied for their ability to serve as pharmacoperones for the vasopressin type 2 receptor (V2R) mutant L83Q, which is known to cause nephrogenic diabetes insipidus (NDI). Three compounds were particularly effective in rerouting the mutant receptor in a concentration-dependent manner, were neither agonists nor antagonists, and displayed low cellular toxicity. Compound 1 was most effective and can be used as a molecular probe for future studies of how small molecules may affect NDI caused by mutant V2R. These compounds, however, failed to rescue the V2R Y128S mutant, indicating that the compounds described may not work in the rescue of all known mutants of V2R. Taken collectively, the present studies have now identified a promising lead compound that could function as a pharmacoperone to correct the trafficking defect of the NDI-associated mutant V2R L83Q and thus has the therapeutic potential for the treatment of NDI.


Assuntos
Chaperonas Moleculares/farmacologia , Sondas Moleculares/farmacologia , Mutação de Sentido Incorreto , Receptores de Vasopressinas/metabolismo , Substituição de Aminoácidos , Diabetes Insípido Nefrogênico/tratamento farmacológico , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/metabolismo , Células HeLa , Humanos , Chaperonas Moleculares/química , Receptores de Vasopressinas/química , Receptores de Vasopressinas/genética
7.
BMC Psychiatry ; 18(1): 227, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-30012135

RESUMO

BACKGROUND: Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15-20% of lithium users and predicts a 2-3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin. METHODS: We will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18-85, who have indicators of NDI, which we defined as urine osmolality (UOsm) < 600 mOsm/kg after 10-h fluid restriction. We will randomize patients to atorvastatin (20 mg/day) or placebo for 12 weeks. We will examine whether this improves measures of NDI: UOsm and aquaporin (AQP2) excretion at 12-week follow-up, adjusted for baseline. RESULTS: Not applicable. CONCLUSION: The aim of this clinical trial is to provide preliminary data about the efficacy of atorvastatin in treating NDI. If successful, lithium could theoretically be used more safely in patients with a reduced subsequent risk of CKD, hypernatremia, and acute kidney injury (AKI). If future definitive trials confirm this, this could potentially allow more patients to benefit from lithium, while minimizing renal risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT02967653 . Registered in February 2017.


Assuntos
Atorvastatina/uso terapêutico , Diabetes Insípido Nefrogênico/induzido quimicamente , Diabetes Insípido Nefrogênico/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Compostos de Lítio/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/epidemiologia , Canadá/epidemiologia , Estudos Transversais , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/epidemiologia , Diabetes Insípido Nefrogênico/epidemiologia , Método Duplo-Cego , Feminino , Humanos , Rim/efeitos dos fármacos , Compostos de Lítio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Nat Commun ; 9(1): 1411, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29650969

RESUMO

Congenital nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine. Congenital NDI is mainly caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R), leading to impaired aquaporin-2 (AQP2) water channel activity. So far, treatment options of congenital NDI either by rescuing mutant V2R with chemical chaperones or by elevating cyclic adenosine monophosphate (cAMP) levels have failed to yield effective therapies. Here we show that inhibition of A-kinase anchoring proteins (AKAPs) binding to PKA increases PKA activity and activates AQP2 channels in cortical collecting duct cells. In vivo, the low molecular weight compound 3,3'-diamino-4,4'-dihydroxydiphenylmethane (FMP-API-1) and its derivatives increase AQP2 activity to the same extent as vasopressin, and increase urine osmolality in the context of V2R inhibition. We therefore suggest that FMP-API-1 may constitute a promising lead compound for the treatment of congenital NDI caused by V2R mutations.


Assuntos
Proteínas de Ancoragem à Quinase A/genética , Aquaporina 2/genética , Compostos Benzidrílicos/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/genética , Diabetes Insípido Nefrogênico/tratamento farmacológico , Fenóis/farmacologia , Proteínas de Ancoragem à Quinase A/antagonistas & inibidores , Proteínas de Ancoragem à Quinase A/metabolismo , Sequência de Aminoácidos , Animais , Aquaporina 2/agonistas , Aquaporina 2/metabolismo , Arginina Vasopressina , Benzazepinas/antagonistas & inibidores , Benzazepinas/farmacologia , Linhagem Celular Transformada , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/metabolismo , Diabetes Insípido Nefrogênico/patologia , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Túbulos Renais Coletores/efeitos dos fármacos , Túbulos Renais Coletores/metabolismo , Túbulos Renais Coletores/patologia , Masculino , Camundongos Endogâmicos C57BL , Concentração Osmolar , Ligação Proteica/efeitos dos fármacos , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/metabolismo , Tolvaptan , Água/metabolismo
10.
Clin Exp Nephrol ; 22(3): 501-507, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29478202

RESUMO

Congenital nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentrating ability. Symptomatic polyuria is present from birth, even with normal release of the antidiuretic hormone vasopressin by the pituitary. Over the last two decades, the aquaporin-2 (AQP2) gene has been cloned and the molecular mechanisms of urine concentration have been gradually elucidated. Vasopressin binds to the vasopressin type II receptor (V2R) in the renal collecting ducts and then activates AQP2 phosphorylation and trafficking to increase water reabsorption from urine. Most cases of congenital NDI are caused by loss-of-function mutations to V2R, resulting in unresponsiveness to vasopressin. In this article, we provide an overview of novel therapeutic molecules of congenital NDI that can activate AQP2 by bypassing defective V2R signaling with a particular focus on the activators of the calcium and cAMP signaling pathways.


Assuntos
Aquaporina 2/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Diabetes Insípido Nefrogênico/tratamento farmacológico , Terapia de Alvo Molecular , Animais , AMP Cíclico/metabolismo , Diabetes Insípido Nefrogênico/metabolismo , Humanos , Inibidores de Fosfodiesterase/uso terapêutico , Receptores Acoplados a Proteínas-G/agonistas
11.
Clin Nephrol ; 89(5): 358-363, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29162216

RESUMO

BACKGROUND: Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder affecting urinary concentration. Clinicians have varied medication regimens as well as nutritional plan approaches for these children. MATERIALS AND METHODS: An electronic survey was distributed to member pediatric nephrologists of the Midwest Pediatric Nephrology Consortium via email (n = 179). Questions included types of drugs prescribed, factors contributing to drug choice, common drug combinations given, and dietary/failure to thrive interventions used. RESULTS: We analyzed results from 72 respondents (42% overall response rate). 72% treated only 1 - 3 patients with NDI per year, 12% treated 4 or more, and 17% had no NDI patients. Of providers treating NDI patients, almost all prescribed thiazides (93%), 62% prescribed amiloride, and 55% reported prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) as part of their drug regimen. gastrointestinal (GI) and renal side effects (43%) were given as reasons for not prescribing indomethacin. For 70%, drug choice was determined by severity of failure to thrive (FTT). Physicians were asked to define the most common drug combinations they prescribed. 48% reported prescribing indomethacin with hydrochlorothiazide. 84% of respondents have a renal dietitian on staff, and half included appointments with a dietitian as part of FTT therapy. The most common intervention for FFT was gastrostomy tube placement (78%). CONCLUSION: Our results suggest consensus on the use of thiazides, while the use of indomethacin is limited by GI and renal side effect profile. Our results revealed that multiple drug combinations are frequently used without one specific preferred regimen.
.


Assuntos
Diabetes Insípido Nefrogênico , Amilorida/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Criança , Diabetes Insípido Nefrogênico/congênito , Diabetes Insípido Nefrogênico/tratamento farmacológico , Combinação de Medicamentos , Humanos , Nefrologistas , Padrões de Prática Médica/estatística & dados numéricos , Tiazidas/uso terapêutico
12.
Handb Exp Pharmacol ; 245: 63-83, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28939971

RESUMO

Pharmacological chaperones recently opened new possibilities in G protein-coupled receptor drug discovery. Even more interestingly, some unique ligands combine pharmacological chaperoning and biased agonism properties, boosting their therapeutic interest in many human diseases resulting from G protein-coupled receptor mutation and misfolding. These compounds displaying dual characteristics would constitute a perfect treatment for congenital Nephrogenic Diabetes Insipidus, a typical conformational disease. This X-linked genetic pathology is mostly associated with inactivating mutations of the renal arginine-vasopressin V2 receptor leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone. Cell-permeable pharmacological chaperones have been successfully challenged to restore plasma membrane localization of many V2 receptor mutants. In addition, different classes of specific ligands such as antagonists, agonists as well as biased agonists of the V2 receptor have proven their usefulness in rescuing mutant receptor function. This is particularly relevant for small-molecule biased agonists which only trigger Gs protein activation and cyclic adenosine monophosphate production, the V2-induced signaling pathway responsible for water reabsorption. In parallel, high-throughput screening assays based on receptor trafficking rescue approaches have been developed to discover novel V2 pharmacological chaperone molecules from different chemical libraries. These new hit compounds, which still need to be pharmacologically characterized and functionally tested in vivo, represent promising candidates for the treatment of congenital Nephrogenic Diabetes Insipidus.


Assuntos
Diabetes Insípido Nefrogênico/tratamento farmacológico , Chaperonas Moleculares/farmacologia , Deficiências na Proteostase/tratamento farmacológico , Receptores de Vasopressinas/fisiologia , Descoberta de Drogas , Humanos , Ligantes , Chaperonas Moleculares/uso terapêutico , Mutação , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/fisiologia , Receptores de Vasopressinas/agonistas , Receptores de Vasopressinas/química
13.
Am J Physiol Renal Physiol ; 313(3): F669-F676, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28615247

RESUMO

Lithium is the mainstay treatment for patients with bipolar disorder, but it generally causes nephrogenic diabetes insipidus (NDI), a disorder in which the renal urine concentrating ability has become vasopressin insensitive. Li-NDI is caused by lithium uptake by collecting duct principal cells and downregulation of aquaporin-2 (AQP2) water channels, which are essential for water uptake from tubular urine. Recently, we found that the prophylactic administration of acetazolamide to mice effectively attenuated Li-NDI. To evaluate whether acetazolamide might benefit lithium-treated patients, we administered acetazolamide to mice with established Li-NDI and six patients with a lithium-induced urinary concentrating defect. In mice, acetazolamide partially reversed lithium-induced polyuria and increased urine osmolality, which, however, did not coincide with increased AQP2 abundances. In patients, acetazolamide led to the withdrawal of two patients from the study due to side effects. In the four remaining patients acetazolamide did not lead to clinically relevant changes in maximal urine osmolality. Urine output was also not affected, although none of these patients demonstrated overt lithium-induced polyuria. In three out of four patients, acetazolamide treatment increased serum creatinine levels, indicating a decreased glomerular filtration rate (GFR). Strikingly, these three patients also showed a decrease in systemic blood pressure. All together, our data reveal that acetazolamide does not improve the urinary concentrating defect caused by lithium, but it lowers the GFR, likely explaining the reduced urine output in our mice and in a recently reported patient with lithium-induced polyuria. The reduced GFR in patients prone to chronic kidney disease development, however, warrants against application of acetazolamide in Li-NDI patients without long-term (pre)clinical studies.


Assuntos
Acetazolamida/uso terapêutico , Diabetes Insípido Nefrogênico/tratamento farmacológico , Diuréticos/uso terapêutico , Capacidade de Concentração Renal/efeitos dos fármacos , Rim/efeitos dos fármacos , Cloreto de Lítio , Poliúria/tratamento farmacológico , Acetazolamida/efeitos adversos , Idoso , Animais , Aquaporina 2/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Diabetes Insípido Nefrogênico/induzido quimicamente , Diabetes Insípido Nefrogênico/fisiopatologia , Modelos Animais de Doenças , Diuréticos/efeitos adversos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Países Baixos , Nova Zelândia , Concentração Osmolar , Projetos Piloto , Poliúria/induzido quimicamente , Poliúria/fisiopatologia , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
14.
Am J Physiol Renal Physiol ; 313(4): F914-F925, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28228402

RESUMO

The direct renin inhibitor aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol·kg dry food-1·day-1 for 4 days and 20 mmol·kg dry food-1·day-1 for the last 3 days) for 7 days. Some mice were intraperitoneally injected with aliskiren (50 mg·kg body wt-1·day-1 in saline). Aliskiren significantly increased protein abundance of aquaporin-2 (AQP2) in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, aliskiren markedly increased AQP2 and phosphorylated AQP2 at serine 256 (pS256-AQP2) protein abundance, which was significantly inhibited both by adenylyl cyclase inhibitor MDL-12330A and by PKA inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in the inner medulla of the kidney. In conclusion, the direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus likely via cAMP-PKA pathways.


Assuntos
Amidas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Aquaporina 2/metabolismo , Diabetes Insípido Nefrogênico/tratamento farmacológico , Fumaratos/uso terapêutico , Túbulos Renais Coletores/efeitos dos fármacos , Amidas/farmacologia , Angiotensina II/urina , Animais , Anti-Hipertensivos/farmacologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fumaratos/farmacologia , Medula Renal/metabolismo , Túbulos Renais Coletores/metabolismo , Lítio , Masculino , Camundongos Endogâmicos C57BL , Poliúria/induzido quimicamente , Poliúria/tratamento farmacológico , Receptores de Superfície Celular/metabolismo
15.
Bull Exp Biol Med ; 162(2): 187-190, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27909962

RESUMO

We performed a complex functional study of the effects of prostaglandin synthesis blockage with diclofenac on manifestation of the hydroosmotic effect of vasopressin V2-receptor agonist desmopressin in the kidneys of Wistar rats with normal synthesis of endogenous vasopressin and homozygous Brattleboro rats with hereditary impaired synthesis of neurohypophyseal hormone vasopressin. Blockage of prostaglandin synthesis led to more pronounced increase in urine osmolality in Brattleboro rats than in Wistar rats due to elevation of not only urine but also sodium gradient at the expense of elimination of the inhibitory effect of prostaglandins on sodium reabsorption and membrane permeability for urine. During combined treatment, the effects of the hormone predominated: the increase in urine osmolality in Wistar and Brattleboro rats did not differ from that after desmopressin administration.


Assuntos
Antidiuréticos/farmacologia , Diabetes Insípido Nefrogênico/tratamento farmacológico , Diclofenaco/farmacologia , Antagonistas de Prostaglandina/farmacologia , Prostaglandinas/biossíntese , Vasopressinas/farmacologia , Animais , Desamino Arginina Vasopressina/farmacologia , Diabetes Insípido Nefrogênico/patologia , Diabetes Insípido Nefrogênico/urina , Córtex Renal/efeitos dos fármacos , Córtex Renal/metabolismo , Córtex Renal/patologia , Medula Renal/efeitos dos fármacos , Medula Renal/metabolismo , Medula Renal/patologia , Concentração Osmolar , Ratos , Ratos Brattleboro , Ratos Wistar , Sódio/urina , Vasopressinas/deficiência
17.
Am J Physiol Renal Physiol ; 311(6): F1149-F1152, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27534996

RESUMO

Fundamental kidney physiology research can provide important insight into how the kidney works and suggest novel therapeutic opportunities to treat human diseases. This is especially true for nephrogenic diabetes insipidus (NDI). Over the past decade, studies elucidating the molecular physiology and signaling pathways regulating water transport have suggested novel therapeutic possibilities. In patients with congenital NDI due to mutations in the type 2 vasopressin receptor (V2R) or acquired NDI due to lithium (or other medications), there are no functional abnormalities in the aquaporin-2 (AQP2) water channel, or in another key inner medullary transport protein, the UT-A1 urea transporter. If it is possible to phosphorylate and/or increase the apical membrane accumulation of these proteins, independent of vasopressin or cAMP, one may be able to treat NDI. Sildenifil (through cGMP), erlotinib, and simvastatin each stimulate AQP2 insertion into the apical plasma membrane. Some recent human data suggest that sildenafil and simvastatin may improve urine concentrating ability. ONO-AE1-329 (ONO) stimulates the EP4 prostanoid receptor (EP4), which stimulates kinases that in turn phosphorylate AQP2 and UT-A1. Clopidogrel is a P2Y12-R antagonist that potentiates the effect of vasopressin and increases AQP2 abundance. Metformin stimulates AMPK to phosphorylate and activate AQP2 and UT-A1, and it increases urine concentrating ability in two rodent models of NDI. Since metformin, sildenafil, and simvastatin are commercially available and have excellent safety records, the potential for rapidly advancing them into clinical trials is high.


Assuntos
Adenilato Quinase/metabolismo , Aquaporina 2/metabolismo , Diabetes Insípido Nefrogênico/tratamento farmacológico , Receptores de Vasopressinas/genética , Animais , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Mutação , Fosforilação/efeitos dos fármacos , Receptores de Vasopressinas/metabolismo , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico
18.
Am J Physiol Renal Physiol ; 311(4): F763-F776, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27385737

RESUMO

Endoplasmic reticulum (ER) stress has been implicated in some types of glomerular and tubular disorders. The objectives of this study were to elucidate the role of ER stress in lithium-induced nephrogenic diabetes insipidus (NDI) and to investigate whether attenuation of ER stress by 4-phenylbutyric acid (4-PBA) improves urinary concentrating defect in lithium-treated rats. Wistar rats received lithium (40 mmol/kg food), 4-PBA (320 mg/kg body wt by gavage every day), or no treatment (control) for 2 wk, and they were dehydrated for 24 h before euthanasia. Lithium treatment resulted in increased urine output and decreased urinary osmolality, which was significantly improved by 4-PBA. 4-PBA also prevented reduced protein expression of aquaporin-2 (AQP2), pS256-AQP2, and pS261-AQP2 in the inner medulla of kidneys from lithium-treated rats after 24-h dehydration. Lithium treatment resulted in increased expression of ER stress markers in the inner medulla, which was associated with dilated cisternae and expansion of ER in the inner medullary collecting duct (IMCD) principal cells. Confocal immunofluorescence studies showed colocalization of a molecular chaperone, binding IgG protein (BiP), with AQP2 in principal cells. Immunohistochemistry demonstrated increased intracellular expression of BiP and decreased AQP2 expression in IMCD principal cells of kidneys from lithium-treated rats. 4-PBA attenuated expression of ER stress markers and recovered ER morphology. In IMCD suspensions isolated from lithium-treated rats, 4-PBA incubation was also associated with increased AQP2 expression and ameliorated ER stress. In conclusion, in experimental lithium-induced NDI, 4-PBA improved the urinary concentrating defect and increased AQP2 expression, likely via attenuating ER stress in IMCD principal cells.


Assuntos
Butilaminas/uso terapêutico , Diabetes Insípido Nefrogênico/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Animais , Aquaporina 2/metabolismo , Butilaminas/farmacologia , Diabetes Insípido Nefrogênico/induzido quimicamente , Diabetes Insípido Nefrogênico/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Lítio , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento , Micção/efeitos dos fármacos
19.
J Biomol Screen ; 21(8): 824-31, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27280550

RESUMO

Pharmacoperones correct the folding of otherwise misfolded protein mutants, restoring function (i.e., providing "rescue") by correcting their trafficking. Currently, most pharmacoperones possess intrinsic antagonist activity because they were identified using methods initially aimed at discovering such functions. Here, we describe an ultra-high-throughput homogeneous cell-based assay with a cAMP detection system, a method specifically designed to identify pharmacoperones of the vasopressin type 2 receptor (V2R), a GPCR that, when mutated, is associated with nephrogenic diabetes insipidus. Previously developed methods to identify compounds capable of altering cellular trafficking of V2R were modified and used to screen a 645,000 compound collection by measuring the ability of library compounds to rescue a mutant hV2R [L83Q], using a cell-based luminescent detection system. The campaign initially identified 3734 positive modulators of cAMP. The confirmation and counterscreen identified only 147 of the active compounds with an EC50 of ≤5 µM. Of these, 83 were reconfirmed as active through independently obtained pure samples and were also inactive in a relevant counterscreen. Active and tractable compounds within this set can be categorized into three predominant structural clusters, described here, in the first report detailing the results of a large-scale pharmacoperone high-throughput screening campaign.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/isolamento & purificação , Diabetes Insípido Nefrogênico/tratamento farmacológico , Ensaios de Triagem em Larga Escala/métodos , Receptores de Vasopressinas/genética , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Diabetes Insípido Nefrogênico/genética , Predisposição Genética para Doença , Humanos , Mutação , Dobramento de Proteína , Transporte Proteico , Receptores de Vasopressinas/isolamento & purificação , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Vasopressinas/genética , Vasopressinas/metabolismo
20.
Am J Physiol Renal Physiol ; 310(10): F1008-12, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26962099

RESUMO

Nephrogenic diabetes insipidus (NDI) is characterized by production of very large quantities of dilute urine due to an inability of the kidney to respond to vasopressin. Congenital NDI results from mutations in the type 2 vasopressin receptor (V2R) in ∼90% of families. These patients do not have mutations in aquaporin-2 (AQP2) or urea transporter UT-A1 (UT-A1). We tested adenosine monophosphate kinase (AMPK) since it is known to phosphorylate another vasopressin-sensitive transporter, NKCC2 (Na-K-2Cl cotransporter). We found AMPK expressed in rat inner medulla (IM). AMPK directly phosphorylated AQP2 and UT-A1 in vitro. Metformin, an AMPK activator, increased phosphorylation of both AQP2 and UT-A1 in rat inner medullary collecting ducts (IMCDs). Metformin increased the apical plasma membrane accumulation of AQP2, but not UT-A1, in rat IM. Metformin increased both osmotic water permeability and urea permeability in perfused rat terminal IMCDs. These findings suggest that metformin increases osmotic water permeability by increasing AQP2 accumulation in the apical plasma membrane but increases urea permeability by activating UT-A1 already present in the membrane. Lastly, metformin increased urine osmolality in mice lacking a V2R, a mouse model of congenital NDI. We conclude that AMPK activation by metformin mimics many of the mechanisms by which vasopressin increases urine-concentrating ability. These findings suggest that metformin may be a novel therapeutic option for congenital NDI due to V2R mutations.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aquaporina 2/metabolismo , Diabetes Insípido Nefrogênico/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Proteínas de Membrana Transportadoras/metabolismo , Metformina/uso terapêutico , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Animais , Diabetes Insípido Nefrogênico/urina , Avaliação Pré-Clínica de Medicamentos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Ureia/metabolismo , Água/metabolismo
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