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1.
Am J Physiol Renal Physiol ; 320(4): F654-F668, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33586496

RESUMO

Chronic kidney disease contributes to hypertension, but the mechanisms are incompletely understood. To address this, we applied the 5/6th nephrectomy rat model to characterize hypertension and the response to dietary salt and renin-angiotensin inhibition. 5/6th nephrectomy caused low-renin, salt-sensitive hypertension with hyperkalemia and unsuppressed aldosterone. Compared with sham rats, 5/6th nephrectomized rats had lower Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, Na+-Cl- cotransporter, α-epithelial Na+ channel (ENaC), and Kir4.1 levels but higher serum and glucocorticoid-regulated kinase 1, prostasin, γ-ENaC, and Kir5.1 levels. These differences correlated with plasma renin, aldosterone, and/or K+. On a normal-salt diet, adrenalectomy (0 ± 9 mmHg) and spironolactone (-11 ± 10 mmHg) prevented a progressive rise in blood pressure (10 ± 8 mmHg), and this was enhanced in combination with losartan (-41 ± 12 and -43 ± 9 mmHg). A high-salt diet caused skin Na+ and water accumulation and aggravated hypertension that could only be attenuated by spironolactone (-16 ± 7 mmHg) and in which the additive effect of losartan was lost. Spironolactone also increased natriuresis, reduced skin water accumulation, and restored vasorelaxation. In summary, in the 5/6th nephrectomy rat chronic kidney disease model, salt-sensitive hypertension develops with a selective increase in γ-ENaC and despite appropriate transporter adaptations to low renin and hyperkalemia. With a normal-salt diet, hypertension in 5/6th nephrectomy depends on angiotensin II and aldosterone, whereas a high-salt diet causes more severe hypertension mediated through the mineralocorticoid receptor.NEW & NOTEWORTHY Chronic kidney disease (CKD) causes salt-sensitive hypertension, but the interactions between dietary salt and the renin-angiotensin system are incompletely understood. In rats with CKD on a normal-salt diet targeting aldosterone, the mineralocorticoid receptor (MR) and especially angiotensin II reduced blood pressure. On a high-salt diet, however, only MR blockade attenuated hypertension. These results reiterate the importance of dietary salt restriction to maintain renin-angiotensin system inhibitor efficacy and specify the MR as a target in CKD.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Renina/farmacologia , Cloreto de Sódio na Dieta/toxicidade , Aldosterona/sangue , Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Ratos , Receptores de Mineralocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/metabolismo , Insuficiência Renal Crônica/induzido quimicamente , Cloreto de Sódio na Dieta/metabolismo , Espironolactona/farmacologia
2.
Actas dermo-sifiliogr. (Ed. impr.) ; 111(8): 639-649, oct. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-197150

RESUMO

La espironolactona es un diurético ahorrador de potasio con efecto antiandrogénico, de bajo coste y con un buen perfil de seguridad. Hemos observado en nuestra experiencia que es un fármaco infrautilizado en dermatología, pese a que existe evidencia de su uso en diversas patologías dermatológicas, especialmente en el acné femenino (nivel de evidencia II-III, fuerza de recomendación B), donde podría disminuir el uso de antibióticos y probablemente de isotretinoína. Otras enfermedades en las cuales puede ser útil son la hidrosadenitis supurativa y la alopecia androgenética femenina. Discutimos las indicaciones de la espironolactona, su dosificación en la práctica dermatológica, las precauciones que deben tener en cuenta y sus efectos secundarios. Además, presentamos nueva evidencia que avala su uso en dermatología sin necesidad de indicar pruebas complementarias en mujeres jóvenes y enfatiza su seguridad a largo plazo. Consideramos que la espironolactona debería estar entre los agentes comúnmente utilizados en la práctica clínica habitual


Spironolactone is an economical potassium-sparing diuretic with an anti-androgenic effect and a good safety profile. Our experience suggests that this diuretic is underexploited in dermatology even though there is evidence supporting its use in several skin conditions. When prescribed for acne in female patients (level 1-2 evidence; strength of recommendation, B), for example, it can reduce the need for antibiotics and possibly isotretinoin. Other diseases in which spironolactone is potentially useful are hidradenitis suppurativa and female androgenetic alopecia. We discuss the indications for spironolactone, dosing in dermatology, precautions to consider, and adverse effects. We also review new evidence that stresses the safety of long-term therapy and supports the use of this drug without the need for complementary testing in young women. We think that spironolactone merits a place among the medications commonly used in routine clinical practice


Assuntos
Humanos , Feminino , Espironolactona/farmacologia , Antagonistas de Androgênios/farmacologia , Acne Vulgar/tratamento farmacológico , Hidradenite Supurativa/tratamento farmacológico , Alopecia/tratamento farmacológico , Hirsutismo/tratamento farmacológico , Resultado do Tratamento
3.
Med Hypotheses ; 143: 110112, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32721806

RESUMO

In coronavirus disease-19 (COVID-19), four major factors have been correlated with worse prognosis: aging, hypertension, obesity, and exposure to androgen hormones. Angiotensin-converting enzyme-2 (ACE2) receptor, regulation of the renin-angiotensin-aldosterone system (RAAS), and transmembrane serine protease 2 (TMPRSS2) action are critical for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cell entry and infectivity. ACE2 expression and RAAS are abnormal in hypertension and obesity, while TMPRSS2 is overexpressed when exposed to androgens, which may justify why these factors are overrepresented in COVID-19. Among therapeutic targets for SARS-CoV-2, we hypothesized that spironolactone, a long used and safe mineralocorticoid and androgen receptors antagonist, with effective anti-hypertensive, cardioprotective, nephroprotective, and anti-androgenic properties may offer pleiotropic actions in different sites to protect from COVID-19. Current data shows that spironolactone may concurrently mitigate abnormal ACE2 expression, correct the balances membrane-attached and free circulating ACE2 and between angiotensin II and Angiotensin-(1-7) (Ang-(1-7)), suppress androgen-mediated TMPRSS2 activity, and inhibit obesity-related RAAS dysfunctions, with consequent decrease of viral priming. Hence, spironolactone may provide protection from SARS-CoV-2, and has sufficient plausibility to be clinically tested, particularly in the early stages of COVID-19.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Androgênios/fisiologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Espironolactona/uso terapêutico , Antagonistas de Androgênios/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Indução Enzimática/efeitos dos fármacos , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Obesidade/complicações , Obesidade/fisiopatologia , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Prognóstico , Receptores Virais/efeitos dos fármacos , Fatores de Risco , Serina Endopeptidases/efeitos dos fármacos , Distribuição por Sexo , Espironolactona/farmacologia , Internalização do Vírus/efeitos dos fármacos
4.
Proc Natl Acad Sci U S A ; 117(23): 13044-13055, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32434920

RESUMO

Epstein-Barr virus (EBV) is associated with epithelial and lymphoid malignancies, establishes latent infection in memory B cells, and intermittently produces infectious virions through lytic replication. Released virions play a key role in latent reservoir maintenance and transmission. Lytic EBV transcription differs from cellular transcription in requiring a virus-encoded preinitiation complex that binds to TATT motifs unique to EBV late lytic promoters. Expression of 15 late lytic genes that are important for virion production and infectivity is particularly dependent on the EBV SM protein, a nuclear protein expressed early during lytic reactivation that binds to viral RNAs and enhances RNA stability. We recently discovered that spironolactone blocks EBV virion production by inhibiting EBV SM function. Since spironolactone causes degradation of xeroderma pigmentosum group B-complementing protein (XPB), a component of human transcription factor TFIIH, in both B lymphocytes and epithelial cells, we hypothesized that SM utilizes XPB to specifically activate transcription of SM target promoters. While EBV SM has been thought to act posttranscriptionally, we provide evidence that SM also facilitates EBV gene transcription. We demonstrate that SM binds and recruits XPB to EBV promoters during lytic replication. Depletion of XPB protein, by spironolactone treatment or by siRNA transfection, inhibits SM-dependent late lytic gene transcription but not transcription of other EBV genes or cellular genes. These data indicate that SM acts as a transcriptional activator that has co-opted XPB to specifically target 15 EBV promoters that have uniquely evolved to require XPB for activity, providing an additional mechanism to differentially regulate EBV gene expression.


Assuntos
DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Herpesvirus Humano 4/genética , Interações Hospedeiro-Patógeno/genética , Fosfoproteínas/metabolismo , Transativadores/metabolismo , Linhagem Celular Tumoral , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/virologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Regiões Promotoras Genéticas/genética , Proteólise/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Espironolactona/farmacologia , Espironolactona/uso terapêutico , Ativação Transcricional/efeitos dos fármacos , Vírion/efeitos dos fármacos , Vírion/metabolismo
6.
PLoS Negl Trop Dis ; 14(3): e0007790, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32168320

RESUMO

Trypanosoma brucei are unicellular parasites endemic to Sub-Saharan Africa that cause fatal disease in humans and animals. Infection with these parasites is caused by the bite of the tsetse fly vector, and parasites living extracellularly in the blood of infected animals evade the host immune system through antigenic variation. Existing drugs for Human and Animal African Trypanosomiasis are difficult to administer and can have serious side effects. Resistance to some drugs is also increasing, creating an urgent need for alternative trypanosomiasis therapeutics. We screened a library of 1,585 U.S. or foreign-approved drugs and identified 154 compounds that inhibit trypanosome growth. As all of these compounds have already undergone testing for human toxicity, they represent good candidates for repurposing as trypanosome therapeutics. In addition to identifying drugs that inhibit trypanosome growth, we wished to identify small molecules that can induce bloodstream form parasites to differentiate into forms adapted for the insect vector. These insect stage parasites lack the immune evasion mechanisms prevalent in bloodstream forms, making them vulnerable to the host immune system. To identify drugs that increase transcript levels of an invariant, insect-stage specific surface protein called procyclin, we engineered bloodstream reporter parasites that express Green Fluorescent Protein (GFP) following induction or stabilization of the procyclin transcript. Using these bloodstream reporter strains in combination with automated flow cytometry, we identified eflornithine, spironolactone, and phenothiazine as small molecules that increase abundance of procyclin transcript. Both eflornithine and spironolactone also affect transcript levels for a subset of differentiation associated genes. While we failed to identify compounds that increase levels of procyclin protein on the cell surface, this study is proof of principle that these fluorescent reporter parasites represent a useful tool for future small molecule or genetic screens aimed at identifying molecules or processes that initiate remodeling of the parasite surface during life cycle stage transitions.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/crescimento & desenvolvimento , Avaliação Pré-Clínica de Medicamentos/métodos , Eflornitina/farmacologia , Fenotiazinas/farmacologia , Espironolactona/farmacologia
7.
Clin Exp Hypertens ; 42(6): 531-538, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32020810

RESUMO

Evidence indicates that renin-angiotensin-aldosterone system (RAS) inhibitors can protect the brain in Alzheimer's disease and Parkinson's disease. The current study evaluated the relationship between aldosterone and tissue damage in the brains of spontaneously hypertensive rats (SHRs) and whether the RAS inhibitor eplerenone can mitigate the damage seen in these rats. SHRs were randomly divided into eplerenone (n = 10) and SHR (n = 10) groups, and Wistar-Kyoto (WKY) rats (n = 10) were used as controls. Eplerenone 50 mg/kg/day was administered orally to the eplerenone group. Pathological changes to the hippocampal formation, plasma and encephalic aldosterone, and plasma potassium levels were compared among the groups. After 10 weeks, rats in the eplerenone and SHR groups showed higher systolic BP (p = .01) than the control group. Aldosterone levels in the brain were higher in the SHR group (0.20 ± 0.06 pg/ml) than in the eplerenone (0.14 ± 0.05 pg/ml, p = .044) or control (0.12 ± 0.07 pg/ml, p = .007) groups. Plasma aldosterone levels in the SHR group were 1.7 times higher than those in the control group (p = .006). Cerebral cortex was thinner in the SHR group (225.18 ± 15.43 µm) than in the eplerenone (240.38 ± 12.85 µm, p < .01) or control (244.72 ± 18.92 µm, p < .01) groups. Thickness did not differ between the latter two groups. The SHR group exhibited apoptotic cells in the hippocampal formation, which were rare in the eplerenone and control groups. Plasma potassium levels were higher in the eplerenone group than those in the other two groups (p < .05). Our results showed that eplerenone can alleviate brain damage (thinning of cortex and increased apoptosis) caused by aldosterone in a rat model of hypertension.


Assuntos
Aldosterona/metabolismo , Encéfalo , Eplerenona/farmacologia , Hipertensão , Animais , Anti-Hipertensivos/farmacologia , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Ratos , Ratos Endogâmicos SHR , Sistema Renina-Angiotensina/efeitos dos fármacos , Espironolactona/farmacologia , Resultado do Tratamento
8.
DNA Repair (Amst) ; 86: 102766, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31838380

RESUMO

UVB radiation results in the formation of potentially mutagenic photoproducts in the DNA of epidermal skin cells. In vitro approaches have demonstrated that the nucleotide excision repair (NER) machinery removes UV photoproducts from DNA in the form of small (∼30-nt-long), excised, damage-containing DNA oligonucleotides (sedDNAs). Though this process presumably takes place in human skin exposed to UVB radiation, sedDNAs have not previously been detected in human skin. Using surgically discarded human skin, we have optimized the detection of the sedDNA products of NER from small amounts of human epidermal tissue ex vivo within minutes of UVB exposure and after UVB doses that normally lead to minimal erythema. Moreover, sedDNA generation was inhibited by treatment of skin explants with spironolactone, which depletes the epidermis of the essential NER protein XPB to mimic the skin of xeroderma pigmentosum patients. Time course experiments revealed that a partially degraded form of the sedDNAs could be readily detected even 12 hours following UVB exposure, which indicates that these repair products are relatively stable in human skin epidermis. Together, these data suggest that sedDNA detection may be a useful assay for determining how genetic, environmental, and other factors influence NER activity in human skin epidermis and whether abnormal sedDNA processing contributes to photosensitive skin disorders.


Assuntos
DNA Helicases/metabolismo , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Oligonucleotídeos/análise , Pele/efeitos da radiação , Dano ao DNA , Relação Dose-Resposta à Radiação , Regulação para Baixo , Humanos , Pele/química , Pele/efeitos dos fármacos , Espironolactona/farmacologia , Raios Ultravioleta
9.
Biomed Pharmacother ; 122: 109695, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31812016

RESUMO

The mechanisms involved in brain damage during chronic glucocorticoid exposure are poorly understood. Since mineralocorticoid receptor (MR) activation has been proven to be important in the pathophysiology of vascular damage and MRs are highly expressed in many brain regions, we hypothesized that the cerebral injury observed in subjects with Cushing syndrome is in part associated with the overactivation of MR. The aim of this study was to determine whether the cerebral injury observed in chronic hyperglucocorticoidemia animal models is related to excessive MR activation. Male SD rats were divided into five groups: vehicle, hydrocortisone (HC, 5 mg/kg/day, i.g.), HC + spironolactone (SL, 20 mg/kg/d in chow), dexamethasone (DXM, 0.25 mg/kg/day, i.g.), and DXM + SL (20 mg/kg/d in chow). Compared to the vehicle-treated group, HC-treated rats had higher blood pressure and higher levels of cerebral vascular fibrosis, cortical/hippocampal atrophy, reactive oxygen species (ROS) production and proinflammatory gene expression. However, in HC-treated animals, treatment with SL markedly alleviated ROS production, cerebral and cerebrovascular morphological changes and inflammation but failed to reduce blood pressure. In contrast, DXM induced no cerebral morphological changes except fibrosis in cerebral vessels, an effect that was not ameliorated by SL treatment. These findings demonstrate that the excessive MR activation observed following chronic hyperglucocorticoidemia exposure contributes to cerebrovascular fibrosis and remodeling and promotes neural apoptosis in the cerebral cortex/hippocampus.


Assuntos
Lesões Encefálicas/metabolismo , Glucocorticoides/metabolismo , Hipocampo/metabolismo , Receptores de Mineralocorticoides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Atrofia/tratamento farmacológico , Atrofia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Lesões Encefálicas/tratamento farmacológico , Dexametasona/farmacologia , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptores de Glucocorticoides/metabolismo , Espironolactona/farmacologia
10.
J Clin Pharm Ther ; 45(1): 152-159, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31520539

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Hashimoto's thyroiditis, also referred to as autoimmune thyroiditis, is characterized by sexual dimorphism, suggesting an important role of sex hormones in its development. No interventional study has investigated whether drugs exerting antiandrogen properties affect thyroid antibody titres and thyroid function tests in subjects with autoimmune thyroiditis. METHODS: This study included 35 levothyroxine-naïve men with euthyroid Hashimoto's thyroiditis. At the physician's discretion, 18 men were then treated with spironolactone (50-200 mg daily), while the remaining patients (n = 17) received other diuretics. Serum levels of thyrotropin, free thyroid hormones, testosterone and 25-hydroxyvitamin D, as well as titres of thyroid peroxidase and thyroglobulin, were measured at the beginning of the study and 6 months later. Based on hormone levels, constant structure parameters of thyroid homeostasis were calculated. RESULTS AND DISCUSSION: At baseline, there was no difference between the treatment arms in terms of thyroid antibody titres, hormone levels and the calculated parameters of thyroid homeostasis. Thirty-two patients completed the study. Spironolactone increased thyroid antibody titres, decreased testosterone and 25-hydroxyvitamin D levels and reduced SPINA-GT. The drug produced a neutral effect on serum levels of thyrotropin, free thyroid hormones, Jostel's thyrotropin index and SPINA-GD. The effect of spironolactone on antibody titres correlated with treatment-induced changes in SPINA-GT, testosterone and 25-hydroxyvitamin D. No significant changes in antibody titres, hormone levels and the calculated parameters of thyroid homeostasis were observed in spironolactone-naïve men. WHAT IS NEW AND CONCLUSION: The obtained results indicate that spironolactone may exert an unfavourable effect on progression of autoimmune thyroiditis in men.


Assuntos
Diuréticos/administração & dosagem , Doença de Hashimoto/tratamento farmacológico , Espironolactona/farmacologia , Idoso , Progressão da Doença , Diuréticos/efeitos adversos , Diuréticos/farmacologia , Relação Dose-Resposta a Droga , Doença de Hashimoto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Espironolactona/administração & dosagem , Espironolactona/efeitos adversos , Testosterona/sangue , Tireoglobulina/sangue , Testes de Função Tireóidea , Hormônios Tireóideos/sangue , Tireotropina/sangue , Vitamina D/análogos & derivados , Vitamina D/sangue
11.
Cells ; 8(12)2019 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-31817997

RESUMO

Aldosterone excess aggravates endothelial dysfunction in diabetes and hypertension by promoting the increased generation of reactive oxygen species, inflammation, and insulin resistance. Aldosterone activates the molecular platform inflammasome in immune system cells and contributes to vascular dysfunction induced by the mineralocorticoid hormone. It is unclear as to whether the NLRP3 inflammasome associated with the mineralocorticoid receptor contributes to vascular dysfunction in diabetic conditions. Here, we tested the hypothesis that an excess of aldosterone induces vascular dysfunction in type 2 diabetes, via the activation of mineralocorticoid receptors (MR) and assembly of the NLRP3 inflammasome. Mesenteric resistance arteries from control (db/m) and diabetic (db/db) mice treated with vehicle, spironolactone (MR antagonist) or an NLRP3 selective inhibitor (MCC950) were used to determine whether NLRP3 contributes to diabetes-associated vascular dysfunction. Db/db mice exhibited increased vascular expression/activation of caspase-1 and IL-1ß, increased plasma IL-1ß levels, active caspase-1 in peritoneal macrophages, and reduced acetylcholine (ACh) vasodilation, compared to db/m mice. Treatment of db/db mice with spironolactone and MCC950 decreased plasma IL-1ß and partly restored ACh vasodilation. Spironolactone also reduced active caspase-1-positive macrophages in db/db mice, events that contribute to diabetes-associated vascular changes. These data clearly indicate that MR and NLRP3 activation contribute to diabetes-associated vascular dysfunction and pro-inflammatory phenotype.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Mineralocorticoides/metabolismo , Animais , Western Blotting , Caspase 1/metabolismo , Citometria de Fluxo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Espironolactona/farmacologia , Sulfonas/farmacologia
12.
Clin Sci (Lond) ; 133(24): 2449-2461, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31799617

RESUMO

Kir5.1 (encoded by the Kcnj16 gene) is an inwardly rectifying K+ (Kir) channel highly expressed in the aldosterone-sensitive distal nephron of the kidney, where it forms a functional channel with Kir4.1. Kir4.1/Kir5.1 channels are responsible for setting the transepithelial voltage in the distal nephron and collecting ducts and are thereby major determinants of fluid and electrolyte distribution. These channels contribute to renal blood pressure control and have been implicated in salt-sensitive hypertension. However, mechanisms pertaining to the impact of K ir4.1/Kir5.1-mediated K+ transport on the renin-angiotensin-aldosterone system (RAAS) remain unclear. Herein, we utilized a knockout of Kcnj16 in the Dahl salt-sensitive rat (SSKcnj16-/-) to investigate the relationship between Kir5.1 and RAAS balance and function in the sensitivity of blood pressure to the dietary Na+/K+ ratio. The knockout of Kcnj16 caused substantial elevations in plasma RAAS hormones (aldosterone and angiotensin peptides) and altered the RAAS response to changing the dietary Na+/K+ ratio. Blocking aldosterone with spironolactone caused rapid mortality in SSKcnj16-/- rats. Supplementation of the diet with high K+ was protective against mortality resulting from aldosterone-mediated mechanisms. Captopril and losartan treatment had no effect on the survival of SSKcnj16-/- rats. However, neither of these drugs prevented mortality of SSKcnj16-/- rats when switched to high Na+ diet. These studies revealed that the knockout of Kcnj16 markedly altered RAAS regulation and function, suggesting Kir5.1 as a key regulator of the RAAS, particularly when exposed to changes in dietary sodium and potassium content.


Assuntos
Túbulos Renais Distais/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Sistema Renina-Angiotensina/efeitos dos fármacos , Aldosterona/sangue , Angiotensinas/sangue , Animais , Pressão Sanguínea , Técnicas de Inativação de Genes , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Potássio na Dieta/administração & dosagem , Ratos Endogâmicos Dahl , Sódio na Dieta/administração & dosagem , Espironolactona/farmacologia
13.
J Renin Angiotensin Aldosterone Syst ; 20(4): 1470320319895933, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856649

RESUMO

OBJECTIVE: Increased circulating level of plasminogen activator inhibitor-1 (PAI-1) is associated with menopausal oestrogen deficiency. We therefore hypothesised that the combined oral contraceptive (COC) with spironolactone (SPL) improves insulin resistance (IR) in ovariectomised (OVX) rats by reducing circulating PAI-1. METHODS: Twelve-week-old female Wistar rats were divided into sham-operated (SHM), OVX, OVX+SPL (0.25 mg/kg), COC (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel) and OVX+COC+SPL rats treated with COC and SPL daily for eight weeks. IR was assessed by homeostatic model assessment of IR (HOMA-IR). RESULTS: Data showed that OVX rats had a higher HOMA-IR value that is associated with increased visceral adiposity, triglycerides (TG), total cholesterol/high-density lipoprotein cholesterol (HDL-C), TG/HDL-C, plasma insulin, GSK-3, corticosterone and decreased 17ß-oestradiol. However, these effects were attenuated in OVX+COC, OVX+SPL and OVX+COC+SPL rats compared to OVX rats. OVX rats had lower PAI-1 than SHM rats, whereas the beneficial effect on IR and other parameters by COC or SPL was accompanied with increased PAI-1. Improvement of IR and other parameters with combined COC and SPL in OVX rats was accompanied with reduced PAI-1. CONCLUSION: Taken together, COC or SPL improves IR independent of PAI-1, whereas a combination of COC and SPL in OVX rats ameliorates IR in a PAI-1-dependent manner.


Assuntos
Etinilestradiol/farmacologia , Resistência à Insulina , Levanogestrel/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Espironolactona/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Corticosterona/sangue , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Dislipidemias/prevenção & controle , Estradiol/sangue , Feminino , Quinase 3 da Glicogênio Sintase/sangue , Ovariectomia , Ratos Wistar
14.
Biochem Biophys Res Commun ; 520(2): 379-384, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31606204

RESUMO

Our previous investigation indicated that angiotensin II (Ang II) enhances the expression of Kv1.5, a promising target for the treatment of atrial fibrillation (AF), by activating reactive oxygen species (ROS)-dependent phosphorylation of Smad 2/3 (forming P-Smad 2/3) and ERK 1/2 (forming P-ERK 1/2). A recent study indicated that aldosterone (Aldo) upregulates atrial Kv1.5 protein in a rat AF model, but the mechanism remains unknown. The present study aimed to clarify the mechanism underlying Aldo-induced Kv1.5 expression and to test whether spironolactone may modulate atrial Kv1.5. Our Western blot analysis indicated that the Aldo/mineralocorticoid receptor (MR) interacts with Ang II/AT1R in upregulating Kv1.5 expression in cultured neonatal atrial myocytes (NRAMs). Blockade of MR with spironolactone and of AT1R with losartan significantly suppressed Kv1.5 expression induction by combined Aldo and Ang II treatment. Aldo increased the protein expression of Nox1, Nox2 and Nox4, but this effect was abolished by spironolactone pretreatment. The Aldo-induced upregulation of Kv1.5 was also reversed by the Src protein tyrosine kinase family inhibitor PP2, the Nox2 inhibitor gp91ds-tat and the Nox1/Nox4 inhibitor GKT137831 but not by the Rac GTPase inhibitor NSC23766. Flow cytometry showed that the Aldo-induced ROS production was inhibited by spironolactone, PP2, gp91ds-tat and GKT137831. Spironolactone suppressed the Aldo-induced protein expression phosphorylated Src (P-Src), P-Smad 2/3 and P-ERK 1/2. In conclusion, we have demonstrated that spironolactone suppresses Aldo-induced Kv1.5 expression by attenuating MR-Nox1/2/4-mediated ROS generation in NRAMs.


Assuntos
Canal de Potássio Kv1.5/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacologia , Aldosterona/farmacologia , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Animais Recém-Nascidos , Átrios do Coração/citologia , NADPH Oxidase 1/metabolismo , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
16.
Am J Physiol Renal Physiol ; 317(6): F1536-F1548, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31588796

RESUMO

The sodium-chloride cotransporter (NCC) in the distal convoluted tubule contributes importantly to sodium balance and blood pressure (BP) regulation. NCC phosphorylation determines transport activity and has a diurnal rhythm influenced by glucocorticoids. Disturbing this rhythm induces "nondipping" BP, an abnormality that increases cardiovascular risk. The receptor through which glucocorticoids regulate NCC is not known. In this study, we found that acute administration of corticosterone to male C57BL6 mice doubled NCC phosphorylation without affecting total NCC abundance in both adrenalectomized and adrenal-intact mice. Corticosterone also increased the whole kidney expression of canonical clock genes: period circadian protein homolog 1 (Per1), Per2, cryptochrome 1, and aryl hydrocarbon receptor nuclear translocator-like protein 1. In adrenal-intact mice, chronic blockade of glucocorticoid receptor (GR) with RU486 did not change total NCC but prevented corticosterone-induced NCC phosphorylation and activation of clock genes. Blockade of mineralocorticoid receptor (MR) with spironolactone reduced the total pool of NCC but did not affect stimulation by corticosterone. The diurnal rhythm of NCC phosphorylation, measured at 6-h intervals, was blunted by chronic GR blockade, and a similar dampening of diurnal variation was seen in GR heterozygous null mice. These effects on NCC phosphorylation did not reflect altered rhythmicity of plasma corticosterone or serum and glucocorticoid-induced kinase 1 activity. Both mineralocorticoids and glucocorticoids emerge as regulators of NCC, acting via distinct receptor pathways. MR activation provides maintenance of the NCC protein pool; GR activation dynamically regulates NCC phosphorylation and establishes the diurnal rhythm of NCC activity. This study has implications for circadian BP homeostasis, particularly in individuals with abnormal glucocorticoid signaling as is found in chronic stress and corticosteroid therapy.


Assuntos
Ritmo Circadiano/fisiologia , Rim/metabolismo , Receptores de Glucocorticoides/metabolismo , Simportadores de Cloreto de Sódio/metabolismo , Adrenalectomia , Animais , Proteínas CLOCK/biossíntese , Proteínas CLOCK/genética , Ritmo Circadiano/efeitos dos fármacos , Corticosterona/sangue , Corticosterona/farmacologia , Rim/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mifepristona/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Fosforilação/efeitos dos fármacos , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/efeitos dos fármacos , Espironolactona/farmacologia
17.
BMC Nephrol ; 20(1): 351, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492107

RESUMO

BACKGROUND: Spironolactone can improve endothelial dysfunction in the setting of heart failure and diabetes models. However, its beneficial effect in the cardiovascular system is not clear in the setting of non-diabetic renal failure. We conducted this study to investigate whether spironolactone can ameliorate endothelial dysfunction in a 5/6 nephrectomy model, and to determine the underlying mechanism. METHODS: Twenty-four Sprague-Dawley rats were divided into four groups. A renal failure model was created using the 5/6 nephrectomy method. The four groups included: Sham-operation group (Group1), chronic kidney disease (CKD; Group2), CKD + ALT-711 (advanced glycation end products [AGEs] breaker; Group 3), and CKD + spironolactone group (Group4). Acetylcholine (Ach)-mediated vasodilatation responses were compared between the four groups. To investigate the underlying mechanism, we cultured human aortic endothelial cells (HAECs) for in-vitro assays. Differences between two groups were determined with the paired student's t test. Differences between three or more groups were determined through one-way analysis of variance (ANOVA) with post-hoc analysis with LSD method. RESULTS: Compared with Group 1, Group 2 has a significantly impaired Ach-mediated vasodilatation response. Group 3 and 4 exhibited improved vasoreactivity responses. To determine the underlying mechanism, we performed an in-vitro study using cultured HAECs. We noted significant sirtuin-3 (SIRT3) protein downregulation, reduced phosphorylation of endothelial nitric oxide synthase at serine 1177 (p-eNOS), and increased intracellular oxidative stress in cultured HAECs treated with AGEs (200 µg/mL). These effects were counter-regulated when cultured HAECs were pretreated with spironolactone (10 µM). Furthermore, the increased p-eNOS production by spironolactone was abrogated when the HAECs were pretreated with tenolvin (1 µM), a SIRT3 inhibitor. CONCLUSIONS: Spironolactone could ameliorate endothelial dysfunction in a 5/6 nephrectomy renal failure model through AGEs/Receptor for AGEs (RAGEs) axis inhibition, SIRT3 upregulation, and nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX-2) and its associated intracellular oxidative stress attenuation.


Assuntos
Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Falência Renal Crônica/tratamento farmacológico , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Espironolactona/uso terapêutico , Animais , Células Cultivadas , Endotélio Vascular/metabolismo , Humanos , Falência Renal Crônica/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Espironolactona/farmacologia
18.
Skin Pharmacol Physiol ; 32(6): 344-348, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31522177

RESUMO

Whilst topical steroids represent one of the most frequently administered treatments for skin and hair diseases, predominantly based on their glucocorticoid receptor-mediated anti-inflammatory effects, the mineralocorticoid effects of topical steroids have received surprisingly little attention. However, the role of mineralocorticoid receptor (MR) signaling is now known to extend beyond the kidney, with human skin, including the hair follicle (HF), expressing the MR. Using microdissected female HFs treated ex vivo with MR agonists and antagonists, we sought to determine the effects of MR-mediated signaling in the cutaneous context. Indeed, not only did the skin and HF epithelium express the MR at both the gene and protein level, but its expression was hair cycle dependent. Moreover, the selective MR antagonist eplerenone promoted hair shaft elongation and hair matrix keratinocyte proliferation whilst delaying catagen (HF regression). These novel observations suggest that the female human HF is sensitive to the inhibition of MR signaling and provide the first evidence that sustained MR signaling may even be required to maintain the growth phase (anagen) of human scalp HFs. Indeed, these data encourage the systematic evaluation of MR agonists and antagonists in human hair growth control so as to identify much-needed, novel anti-hirsutism and/or hair growth-promoting agents, respectively.


Assuntos
Cabelo/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Adulto , Idoso , Aldosterona/farmacologia , Eplerenona/farmacologia , Feminino , Cabelo/crescimento & desenvolvimento , Cabelo/metabolismo , Humanos , Pessoa de Meia-Idade , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacologia
19.
DNA Cell Biol ; 38(10): 1134-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433203

RESUMO

Diabetes mellitus is a complicated metabolic disease characterized by hyperglycemia. Diabetic nephropathy (DN) is a progressive kidney disease, which results in mortality in diabetic patients. The present study was designed to investigate the effect of applying spironolactone (S), captopril (C), and their combination (S+C) on some renal performance indices and microRNAs' (miRNAs) expression. A total of 35 two-month-old male Wistar rats were provided for the study. Intraperitoneal injection of freshly dissolved streptozotocin (60 mg/kg) in cold citrate buffer was used to induce diabetes. Blood samples were examined through calorimetry to assess serum concentrations of glucose, blood urea nitrogen (BUN), and creatinine. To measure the microalbuminuria and transforming growth factor-ß (TGF-ß) levels and to evaluate the miRNAs expression levels of the kidney tissue, the ELISA method and the real-time PCR were used. The obtained results serve as in vivo evidence for the positive relationship between miR-192 and TGF-ß levels in the DN rats. A significant increase and decrease were found for miR-29a/b/c and the miR-192 expression of DN after treatment with S, C, and S+C. TGF-ß levels and microalbuminuria of diabetic rats also increased. The results obtained from this research study suggest that S, C, and S + C can improve DN by targeting miR-192 and miR-29 family and changing their expression. These findings suggest that miR-192 and miRs-29a/b/c can be potential targets for DN remediation.


Assuntos
Captopril/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Espironolactona/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Diuréticos/farmacologia , Combinação de Medicamentos , Reposicionamento de Medicamentos , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
20.
Chem Biol Interact ; 310: 108742, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31295448

RESUMO

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women of reproductive age and hyperandrogenism is a prominent feature of PCOS resulting in infertility and increased risk of developing metabolic disorders including insulin resistance (IR), abdominal adiposity, glucose intolerance and cardiovascular diseases. Spironolactone (SPL), a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. In this study, we investigated the effects of SPL on IR and metabolic disturbances in letrozole-induced PCOS rats. Eighteen adults female Wistar rats were randomly divided into 3 groups and treated with vehicle, letrozole (LET; 1 mg/kg) and LET + SPL (SPL; 0.25 mg/kg), p.o. once daily for 21 consecutive days. Results showed that LET treatment induced PCOS characterised by elevated plasma testosterone and luteinizing hormone (LH) accompanied with increased body weight and visceral adiposity, IR, glucose intolerance, dyslipidemia and altered histomorphological ovaries. Treatment with SPL however attenuated the elevated testosterone in LET-induced PCOS model accompanied with a reversal in all the observed alterations. Taken together, analysis of the physical, biochemical and histological evidences shows that the protective effect of this very low dose spironolactone may be through its anti-androgenic mechanism.


Assuntos
Resistência à Insulina , Síndrome do Ovário Policístico/tratamento farmacológico , Espironolactona/farmacologia , Testosterona/sangue , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Animais , Feminino , Letrozol , Hormônio Luteinizante/sangue , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Ratos , Ratos Wistar , Espironolactona/uso terapêutico
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