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1.
PLoS One ; 16(1): e0244978, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33406133

RESUMO

The location-based services can provide users with the requested location information. But users also need to disclose their current location to the location-based service provider. Therefore, how to protect user's location privacy is a major concern. In this paper, we propose a heterogeneous deniable authenticated encryption scheme called HDAE for location-based services. The proposed scheme permits a sender in a public key infrastructure environment to transmit a message to a receiver in an identity-based environment. Our design utilizes a hybrid encryption method combing the tag-key encapsulation mechanism (tag-KEM) and the data encapsulation mechanism (DEM), which is well adopted for location-based services applications. We give how to design an HDAE scheme utilizing a heterogeneous deniable authenticated tag-KEM (HDATK) and a DEM. We also construct an HDATK scheme and provide security proof in the random oracle model. Comprehensive analysis shows that our scheme is efficient and secure. In addition, we give an application of the HDAE to a location-based services system.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33407017

RESUMO

Recent evidence indicates a crucial role for G protein-coupled estrogen receptor 1 (GPER1) in the maintenance of cardiovascular and kidney health in females. The current study tested whether GPER1 activation ameliorates hypertension and kidney damage in female Dahl salt-sensitive (SS) rats fed a high-salt (HS) diet. Adult female rats were implanted with telemetry transmitters for monitoring blood pressure and osmotic minipumps releasing G1 (selective GPER1 agonist, 400 µg/kg/day, intraperitoneal) or vehicle. Two weeks after pump implantation, rats were shifted from a normal salt diet (NS, 0.4% NaCl) to a matched HS diet (4.0% NaCl) for 2 weeks. 24-hour urine samples were collected during both diet periods and urinary markers of kidney injury were assessed. Histological assessment of kidney injury was conducted after the 2-week HS diet period. Compared with values during the NS diet, 24-hour mean arterial pressure markedly increased in response to HS, reaching similar values in vehicle-treated and G1-treated rats. HS also significantly increased urinary excretion of protein, albumin, nephrin (podocyte damage marker) and KIM-1 (proximal tubule injury marker) in vehicle-treated rats. Importantly, G1 treatment prevented the HS-induced proteinuria, albuminuria and increase in KIM-1 excretion but not nephrinuria. Histological analysis revealed that HS-induced glomerular damage did not differ between groups. However, G1 treatment preserved proximal tubule brush border integrity in HS-fed rats. Collectively, our data suggest that GPER1 activation protects against HS-induced proteinuria and albuminuria in female Dahl SS rats by preserving proximal tubule brush border integrity in a blood pressure-independent manner.

3.
Cancer Chemother Pharmacol ; 86(5): 663-672, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33030583

RESUMO

PURPOSE: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA which has been identified to be involved in alternative non-homologous end joining (A-NHEJ) pathways by binding with PARP1 and LIG3 in myeloma cells. This study aims to explore the roles of MALAT1 in DNA repair processes in non-small cell lung cancer (NSCLC). METHODS: The interactions between MALAT1 and proteins were identified by co-immunoprecipitation and RNA pulldown. The interactions between MALAT1 and microRNAs (miRNA) were predicted by bioinformatics tools and confirmed by luciferase assay and RNA pulldown. The DNA damages were quantified by comet assay. The cell viability was examined by MTT assay and the cell apoptosis was determined by flow cytometry. RESULTS: MALAT1 is identified to be involved in A-NHEJ pathway in NSCLC cells. However, in LIG3-null cells where A-NHEJ pathway is inactivated, targeting MALAT1 still increases DNA damages, suggesting that MALAT1 participates in other DNA repair pathways. Subsequently, MALAT1 is identified to bind with miR-146a and miR-216b, which directly target the 3'UTR of BRCA1. MALAT1 is confirmed to functions as a competing endogenous RNA (ceRNA) absorbing miR-146a and miR-216b, upregulating BRCA1 expression and protecting Homologous Recombination (HR) pathway in NSCLC cells. Finally, overexpression MALAT1 protects NSCLC cells from the cytotoxic effect of cisplatin. While, targeting MALAT1 in NSCLC cells induces DNA damages by repressing HR pathway and sensitizes NSCLC cells to cisplatin which had the potential for NSCLC treatment. CONCLUSION: MALAT1 is involved in HR pathway by protecting BRCA1 and targeting MALAT1 induces DNA damages in NSCLC.

4.
JCI Insight ; 5(16)2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32673289

RESUMO

Histone deacetylase (HDAC) enzymes regulate transcription through epigenetic modification of chromatin structure, but their specific functions in the kidney remain elusive. We discovered that the human kidney expresses class I HDACs. Kidney medulla-specific inhibition of class I HDACs in the rat during high-salt feeding results in hypertension, polyuria, hypokalemia, and nitric oxide deficiency. Three new inducible murine models were used to determine that HDAC1 and HDAC2 in the kidney epithelium are necessary for maintaining epithelial integrity and maintaining fluid-electrolyte balance during increased dietary sodium intake. Moreover, single-nucleus RNA-sequencing determined that epithelial HDAC1 and HDAC2 are necessary for expression of many sodium or water transporters and channels. In performing a systematic review and meta-analysis of serious adverse events associated with clinical HDAC inhibitor use, we found that HDAC inhibitors increased the odds ratio of experiencing fluid-electrolyte disorders, such as hypokalemia. This study provides insight on the mechanisms of potential serious adverse events with HDAC inhibitors, which may be fatal to critically ill patients. In conclusion, kidney tubular HDACs provide a link between the environment, such as consumption of high-salt diets, and regulation of homeostatic mechanisms to remain in fluid-electrolyte balance.

5.
J Am Heart Assoc ; 9(10): e015110, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32390531

RESUMO

Background The novel estrogen receptor, G-protein-coupled estrogen receptor (GPER), is responsible for rapid estrogen signaling. GPER activation elicits cardiovascular and nephroprotective effects against salt-induced complications, yet there is no direct evidence for GPER control of renal Na+ handling. We hypothesized that GPER activation in the renal medulla facilitates Na+ excretion. Methods and Results Herein, we show that infusion of the GPER agonist, G1, to the renal medulla increased Na+ excretion in female Sprague Dawley rats, but not male rats. We found that GPER mRNA expression and protein abundance were markedly higher in outer medullary tissues from females relative to males. Blockade of GPER in the renal medulla attenuated Na+ excretion in females. Given that medullary endothelin 1 is a well-established natriuretic factor that is regulated by sex and sex steroids, we hypothesized that GPER activation promotes natriuresis via an endothelin 1-dependent pathway. To test this mechanism, we determined the effect of medullary infusion of G1 after blockade of endothelin receptors. Dual endothelin receptor subtype A and endothelin receptor subtype B antagonism attenuated G1-induced natriuresis in females. Unlike males, female mice with genetic deletion of GPER had reduced endothelin 1, endothelin receptor subtype A, and endothelin receptor subtype B mRNA expression compared with wild-type controls. More important, we found that systemic GPER activation ameliorates the increase in mean arterial pressure induced by ovariectomy. Conclusions Our data uncover a novel role for renal medullary GPER in promoting Na+ excretion via an endothelin 1-dependent pathway in female rats, but not in males. These results highlight GPER as a potential therapeutic target for salt-sensitive hypertension in postmenopausal women.

6.
Hypertension ; 75(6): 1624-1634, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32306766

RESUMO

The diurnal rhythms of sodium handling and blood pressure are thought to be regulated by clock genes, such as Bmal1. However, little is known about the regulation of these factors by Bmal1, especially in rats. Using a novel whole-body Bmal1 knockout rat model (Bmal1-/-), we hypothesized that time of day regulation of sodium excretion is dependent on Bmal1. Using telemetry to continuously record mean arterial pressure, we observed that male and female Bmal1-/- rats had significantly reduced mean arterial pressure over the course of 24 hours compared with littermate controls. The circadian mean arterial pressure pattern remained intact in both sexes of Bmal1-/- rats, which is in contrast to the Bmal1-/- mouse model. Male Bmal1-/- rats had no significant difference in baseline sodium excretion between 12-hour active and inactive periods, indicating a lack of diurnal control independent of maintained mean arterial pressure rhythms. Female Bmal1-/- rats, however, had significantly greater sodium excretion during the active versus inactive period similar to controls. Thus, we observed a clear dissociation between circadian blood pressure and control of sodium excretion that is sex dependent. These findings are consistent with a more robust ability of females to maintain control of sodium excretion, and furthermore, demonstrate a novel role for Bmal1 in control of diurnal blood pressure independent of sodium excretion.

7.
Front Genet ; 11: 168, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32174980

RESUMO

Objective: This study reports a Chinese patient with a Congenital Disorder of Glycosylation (CDG) caused by compound-heterozygous mutations in the Conserved Oligomeric Golgi 5 (COG5) gene and thereby offers concrete evidence for early diagnosis. Methods: The clinical manifestations, the results of laboratory examinations and genetic analysis of a 4-year-old Chinese girl with CDG are reported. We also reviewed previous CDG cases that involved COG5 mutations by comparing the phenotypes and genotypes in different cases. Results: The patient was admitted to our hospital due to ataxia and psychomotor delay. The major clinical manifestations were postural instability, difficulty in walking, psychomotor delay, hypohidrosis, hyperkeratosis of the skin, and ulnar deviation of the right-hand fingers. Biochemical analyses revealed coagulation defect and liver lesions. Vision tests showed choroidopathy and macular hypoplasia. Whole-exome sequencing identified the hitherto unreported compound-heterozygous COG5 mutations, c.1290C > A (p.Y430X) and c.2077A > C (p.T693P). Mutation p.Y430X is nonsense, leading to a truncated protein. Mutation p.T693P is located at a highly conserved region, and thus the polar-to-non-polar substitution presumably affects the structure and function of COG5. According to the Human Genome Mutation Database Professional, there have been totally 13 CDG cases caused by 13 COG5 mutations. They are mainly characterized by psychomotor delay, hypotonia, ataxia, microcephaly, and hearing and visual abnormalities. Conclusion: The clinical manifestations of the patient are mild but consistent with the clinical characteristics of the published COG5-CDG cases. The results of this study extend the spectrum of clinical and genetic findings in COG5-CDG.

8.
Am J Physiol Renal Physiol ; 318(3): F710-F719, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31904281

RESUMO

Kidney function follows a 24-h rhythm subject to regulation by circadian genes including the transcription factor Bmal1. A high-salt diet induces a phase shift in Bmal1 expression in the renal inner medulla that is dependent on endothelin type B (ETB) receptors. Furthermore, ETB receptor-mediated natriuresis is sex dependent. Therefore, experiments tested the hypothesis that collecting duct Bmal1 regulates blood pressure in a sex-dependent manner. We generated a mouse model that lacks Bmal1 expression in the collecting duct, where ETB receptor abundance is highest. Male, but not female, collecting duct Bmal1 knockout (CDBmal1KO) mice had significantly lower 24-h mean arterial pressure (MAP) than flox controls (105 ± 2 vs. 112 ± 3 mmHg for male mice and 106 ± 1 vs. 108 ± 1 mmHg for female mice, by telemetry). After 6 days on a high-salt (4% NaCl) diet, MAP remained significantly lower in male CDBmal1KO mice than in male flox control mice (107 ± 2 vs. 113 ± 1 mmHg), with no significant differences between genotypes in female mice (108 ± 2 vs. 109 ± 1 mmHg). ETB receptor blockade for another 6 days increased MAP similarly in both male and female CDBmal1KO and flox control mice. However, MAP remained lower in male CDBmal1KO mice than in male flox control mice (124 ± 2 vs. 130 ± 2 mmHg). No significant differences were observed between female CDBmal1KO and flox mice during ETB blockade (130 ± 2 vs. 127 ± 2 mmHg). There were no significant genotype differences in amplitude or phase of MAP in either sex. These data suggest that collecting duct Bmal1 has no role in circadian MAP but plays an important role in overall blood pressure in male, but not female, mice.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Pressão Sanguínea/fisiologia , Regulação da Expressão Gênica/fisiologia , Túbulos Renais Coletores/metabolismo , Fatores de Transcrição ARNTL/genética , Aldosterona/metabolismo , Aldosterona/urina , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Potássio/urina , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Fatores Sexuais , Sódio/metabolismo , Sódio/urina , Cloreto de Sódio na Dieta/administração & dosagem
9.
Acta Physiol (Oxf) ; 226(1): e13227, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30501003

RESUMO

AIM: Chronic high salt intake exaggerates renal injury and inflammation, especially with the loss of functional ETB receptors. Tauroursodeoxycholic acid (TUDCA) is a chemical chaperone and bile salt that is approved for the treatment of hepatic diseases. Our aim was to determine whether TUDCA is reno-protective in a model of ETB receptor deficiency with chronic high salt-induced renal injury and inflammation. METHODS: ETB -deficient and transgenic control rats were placed on normal (0.8% NaCl) or high salt (8% NaCl) diet for 3 weeks, receiving TUDCA (400 mg/kg/d; ip) or vehicle. Histological and biochemical markers of kidney injury, renal cell death and renal inflammation were assessed. RESULTS: In ETB -deficient rats, high salt diet significantly increased glomerular and proximal tubular histological injury, proteinuria, albuminuria, excretion of tubular injury markers KIM-1 and NGAL, renal cortical cell death and renal CD4+ T cell numbers. TUDCA treatment increased proximal tubule megalin expression as well as prevented high salt diet-induced glomerular and tubular damage in ETB -deficient rats, as indicated by reduced kidney injury markers, decreased glomerular permeability and proximal tubule brush border restoration, as well as reduced renal inflammation. However, TUDCA had no significant effect on blood pressure. CONCLUSIONS: TUDCA protects against the development of glomerular and proximal tubular damage, decreases renal cell death and inflammation in the renal cortex in rats with ETB receptor dysfunction on a chronic high salt diet. These results highlight the potential use of TUDCA as a preventive tool against chronic high salt induced renal damage.


Assuntos
Inflamação/induzido quimicamente , Nefropatias/induzido quimicamente , Cloreto de Sódio na Dieta/administração & dosagem , Cloreto de Sódio na Dieta/efeitos adversos , Ácido Tauroquenodesoxicólico/farmacologia , Animais , Animais Geneticamente Modificados , Deleção de Genes , Inflamação/prevenção & controle , Nefropatias/prevenção & controle , Masculino , Distribuição Aleatória , Ratos , Receptor de Endotelina B/genética
10.
PLoS One ; 13(12): e0208311, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30562351

RESUMO

A smart grid, considered the next-generation type of power grid, combines a traditional power grid with information and communication technologies to effectively facilitate power generation and ensure transmission security and reliability in real-time. Only authorized consumers should be able to access the smart grid because the information gathered by smart meters includes users' private information. However, smart grid security is still a challenge. Motivated by this challenge, in this paper, we propose a heterogeneous signcryption (HSC) scheme for secure communication between smart meters and the utility. We demonstrate that this scheme is indistinguishable against adaptive chosen-ciphertext attacks (IND-CCA2), existentially unforgeable against adaptive chosen-message attacks (EUF-CMA) and ciphertext-anonymous against adaptive chosen ciphertext attacks (ANON-CCA2) under the computational Diffie-Hellman (CDH) problem in the random oracle model. Our scheme simultaneously achieves confidentiality, integrity, authentication, non-repudiation and ciphertext anonymity in a single logical step. It supports heterogeneous systems, allowing a meter in an identity-based cryptography (IBC) environment to transmit electrical usage data to a utility in a public key infrastructure (PKI) environment. Compared with other existing related schemes, our scheme has the lowest communication overhead and energy consumption for the smart grid. Based on these features, our scheme is highly suitable for secure power transmissions in a smart grid.


Assuntos
Algoritmos , Redes de Comunicação de Computadores , Segurança Computacional
11.
Math Biosci Eng ; 15(6): 1345-1385, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30418789

RESUMO

In this paper, we derive a chemotaxis model with degenerate diffusion and density-dependent chemotactic sensitivity, and we provide a more realistic description of cell migration process for its early and late stages. Different from the existing studies focusing on the case of non-degenerate diffusion, this model with degenerate diffusion causes us some essential difficulty on the boundedness estimates and the propagation behavior of its compact support. In the presence of logistic damping, for the early stage before tumour cells spread to the whole domain, we first estimate the expanding speed of tumour region as O(t^ß) for 0 < ß < 1/2 . Then, for the late stage of cell migration, we further prove that the asymptotic profile of the original system is just its corresponding steady state. The global convergence of the original weak solution to the steady state with exponential rate O(e^(-ct)) for some c < 0 is also obtained.


Assuntos
Quimiotaxia/fisiologia , Modelos Biológicos , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Matriz Extracelular/patologia , Matriz Extracelular/fisiologia , Humanos , Modelos Lineares , Conceitos Matemáticos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Neoplasias/patologia , Neoplasias/fisiopatologia , Dinâmica não Linear , Esferoides Celulares/patologia , Esferoides Celulares/fisiologia
12.
Dev Comp Immunol ; 89: 1-6, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30076875

RESUMO

The F-type lectin (fucolectin) family represents a new group with innate immunity. In this study, two fucolectin isoforms (designated as AjFTL-1 and AjFTL-2) were identified in sea cucumber (Apostichopus japonicus) through rapid amplification of cDNA ends. Full-length cDNAs of AjFTL-1 and AjFTL-2 measured 2134 and 1286 bp, encoding two secreted proteins comprising 317 and 181 amino acid residues, respectively. The signal peptide, l-fucose binding motif ("HX(26)RXDX(4)R/K") and cation binding sequence motif ("h2DGx") were conserved in AjFTL-1 and AjFTL-2. However, AjFTL-1 contains an additional complement control protein domain. Multiple sequence alignments supported that AjFTL-1 and AjFTL-2 are new members of the F-type lectin family. Tissues distribution analysis indicated that both AjFTL-1 and AjFTL-2 were widely expressed in all tested tissues, featuring differential expression patterns. Vibrio splendidus infection in vivo can significantly upregulate the mRNA transcripts of the two genes, with a larger magnitude observed in AjFTL-1. By contrast, lipopolysaccharide stimulation in vitro can markedly induce the expression level of AjFTL-2 but not that of AjFTL-1. Silencing AjFTL-2 by siRNA can suppress the AjNOS transcript, whereas injection of the recombinant protein of AjFTL-2 can significantly induce AjNOS expression. By contrast, the loss- and gain-of-function of AjFTL-1 caused no effect on the expression of AjNOS. Our present study provides evidence supporting that AjFTL-1 and AjFTL-2 play diverse roles in the innate immune defense of sea cucumbers toward bacterial infection.


Assuntos
Lectinas/imunologia , Stichopus/imunologia , Animais , Clonagem Molecular , DNA Complementar/genética , Expressão Gênica , Imunidade Inata/genética , Lectinas/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Stichopus/genética , Stichopus/microbiologia , Distribuição Tecidual , Vibrio/patogenicidade
13.
J Med Syst ; 42(8): 143, 2018 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-29959607

RESUMO

Wireless body area networks (WBANs) comprises a number of sensor nodes and the portable mobile device such as smartphone. It is used to monitor the physical condition and provide a reliable healthcare system. Utilizing the wireless communication network, sensor nodes collect the physiological data of one patient to the portable mobile device and the latter analyzes and transmits them to the application providers. Therefore, the personal data confidentiality and user privacy are cores of WBANs. Recently, Shen et al. presented a multi-layer authentication protocol for WBANs, which is lightweight and much easier to implement. However, we observe that their authentication between sensor nodes and the portable mobile device could ensure the forward security property only when the sensor nodes are changed (add or delete). When the sensor nodes are constant, the security property is not satisfied. Meanwhile, the authentication between the portable mobile device and application provider is prone to mutual impersonation attack, so the critical goal of mutual authentication can not be achieved. In this paper, an improved two-layer authentication scheme is proposed to remove the flaws. The analysis shows that our method is more secure and could withstand various attacks.


Assuntos
Segurança Computacional , Dispositivos Eletrônicos Vestíveis , Tecnologia sem Fio , Redes de Comunicação de Computadores , Confidencialidade , Humanos , Privacidade , Telemetria
14.
Genes Genomics ; 40(6): 603-613, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29892942

RESUMO

Quantitative real-time PCR (qRT-PCR) is a standard method to measure gene expression in function exploring. Accurate and reproducible data of qRT-PCR requires appropriate reference genes, which are stably expressed under different experimental conditions. However, no housekeeping genes were validated as internal controls for qRT-PCR in Sinonovacula constricta. In this study, we classified the transcriptome data of two tissues for Vibrio infection and Cd2+ stress into ten clusters based on the gene expression patterns. Among them, cluster 5 had the most stable gene expression patterns regardless of tissues and treatments as the database for candidate reference genes. A total of 55 orthologs of classical housekeeping genes in the clam transcriptome were annotated. Combined the expression profiles and housekeeping genes in S. constricta, we chose eight candidate reference genes and validated their expression in Vibrio-infected samples and different tissues by qRT-PCR. Their expression stability was analyzed by three different algorithms geNorm, NormFinder and BestKeeper. Although the rank of the eight candidate reference genes is different in different treatments using different software, RS9 could be the best reference genes for normalization of qRT-PCR expression data in S. constricta under various treatments considering the above analysis. Meanwhile, the ranking of genes based on the CV values of transcriptomic data was similar to the validation results. This study provides for the first time a list of suitable reference genes for S. constricta and a valuable resource for further studies of clam immune defense systems.


Assuntos
Bivalves/genética , Perfilação da Expressão Gênica/métodos , Animais , Reação em Cadeia da Polimerase em Tempo Real/métodos , Padrões de Referência , Reprodutibilidade dos Testes , Transcriptoma
15.
J Med Syst ; 42(6): 108, 2018 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-29705947

RESUMO

Wireless body area network (WBAN) provides a medium through which physiological information could be harvested and transmitted to application provider (AP) in real time. Integrating WBAN in a heterogeneous Internet of Things (IoT) ecosystem would enable an AP to monitor patients from anywhere and at anytime. However, the IoT roadmap of interconnected 'Things' is still faced with many challenges. One of the challenges in healthcare is security and privacy of streamed medical data from heterogeneously networked devices. In this paper, we first propose a heterogeneous signcryption scheme where a sender is in a certificateless cryptographic (CLC) environment while a receiver is in identity-based cryptographic (IBC) environment. We then use this scheme to design a heterogeneous access control protocol. Formal security proof for indistinguishability against adaptive chosen ciphertext attack and unforgeability against adaptive chosen message attack in random oracle model is presented. In comparison with some of the existing access control schemes, our scheme has lower computation and communication cost.


Assuntos
Segurança Computacional , Monitorização Ambulatorial/métodos , Telemetria/métodos , Tecnologia sem Fio , Algoritmos , Confidencialidade , Humanos , Tecnologia de Sensoriamento Remoto/métodos
16.
Clin Sci (Lond) ; 132(11): 1179-1197, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29650676

RESUMO

Sodium bicarbonate (NaHCO3) slows the decline in kidney function in patients with chronic kidney disease (CKD), yet the mechanisms mediating this effect remain unclear. The Dahl salt-sensitive (SS) rat develops hypertension and progressive renal injury when fed a high salt diet; however, the effect of alkali loading on kidney injury has never been investigated in this model. We hypothesized that NaHCO3 protects from the development of renal injury in Dahl salt-sensitive rats via luminal alkalization which limits the formation of tubular casts, which are a prominent pathological feature in this model. To examine this hypothesis, we determined blood pressure and renal injury responses in Dahl SS rats drinking vehicle (0.1 M NaCl) or NaHCO3 (0.1 M) solutions as well as in Dahl SS rats lacking the voltage-gated proton channel (Hv1). We found that oral NaHCO3 reduced tubular NH4+ production, tubular cast formation, and interstitial fibrosis in rats fed a high salt diet for 2 weeks. This effect was independent of changes in blood pressure, glomerular injury, or proteinuria and did not associate with changes in renal inflammatory status. We found that null mutation of Hv1 also limited cast formation in Dahl SS rats independent of proteinuria or glomerular injury. As Hv1 is localized to the luminal membrane of TAL, our data suggest that alkalization of the luminal fluid within this segment limits cast formation in this model. Reduced cast formation, secondary to luminal alkalization within TAL segments may mediate some of the protective effects of alkali loading observed in CKD patients.


Assuntos
Glomerulosclerose Segmentar e Focal/prevenção & controle , Túbulos Renais/patologia , Proteinúria/prevenção & controle , Bicarbonato de Sódio/uso terapêutico , Ácidos/urina , Animais , Glicemia/metabolismo , Modelos Animais de Doenças , Fibrose , Glomerulosclerose Segmentar e Focal/etiologia , Glomerulosclerose Segmentar e Focal/metabolismo , Hemodinâmica/efeitos dos fármacos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Canais Iônicos/deficiência , Canais Iônicos/genética , Canais Iônicos/fisiologia , Masculino , Proteinúria/metabolismo , Ratos Endogâmicos Dahl , Ratos Mutantes , Bicarbonato de Sódio/farmacologia , Cloreto de Sódio na Dieta/farmacologia , Cloreto de Sódio na Dieta/toxicidade
17.
J Am Heart Assoc ; 7(4)2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29453306

RESUMO

BACKGROUND: Acute psychosocial stress provokes increases in circulating endothelin-1 (ET-1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress-induced ET-1 remain unanswered. We hypothesized that endothelium-derived ET-1 contributes to the acute pressor response to stress via activation of the endothelin A receptor. METHODS AND RESULTS: Adult male vascular endothelium-specific ET-1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in both genotypes; however, this response was significantly blunted in vascular endothelium-specific ET-1 knockout mice compared with control mice that were homozygous for the floxed allele. In mice pretreated for 3 days with the endothelin A antagonist, ABT-627, or the dual endothelin A/B receptor antagonist, A-182086, the pressor response to CSS was similar between genotypes. CSS significantly increased plasma ET-1 levels in control mice that were homozygous for the floxed allele. CSS failed to elicit an increase in plasma ET-1 in vascular endothelium-specific ET-1 knockout mice. Telemetry frequency domain analyses suggested similar autonomic responses to stress between genotypes, and isolated resistance arteries demonstrated similar sensitivity to α1-adrenergic receptor-mediated vasoconstriction. CONCLUSIONS: These findings specify that acute stress-induced activation of endothelium-derived ET-1 and subsequent endothelin A receptor activation is a novel mediator of the blood pressure response to acute psychosocial stress.


Assuntos
Aorta Torácica/metabolismo , Endotelina-1/metabolismo , Artérias Mesentéricas/metabolismo , Estresse Psicológico/metabolismo , Vasoconstrição , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Pressão Arterial , Modelos Animais de Doenças , Antagonistas do Receptor de Endotelina A/farmacologia , Endotelina-1/deficiência , Endotelina-1/genética , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Camundongos Knockout , Receptor de Endotelina A/efeitos dos fármacos , Receptor de Endotelina A/metabolismo , Transdução de Sinais , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Sistema Nervoso Simpático/fisiopatologia , Vasoconstrição/efeitos dos fármacos
18.
Am J Physiol Renal Physiol ; 314(1): F89-F98, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28971988

RESUMO

Speed JS, Hyndman KA, Roth K, Heimlich JB, Kasztan M, Fox BM, Johnston JG, Becker BK, Jin C, Gamble KL, Young ME, Pollock JS, Pollock DM. High dietary sodium causes dyssynchrony of the renal molecular clock in rats. Am J Physiol Renal Physiol 314: F89-F98, 2018. First published September 27, 2017; doi:10.1152/ajprenal.00028.2017.-Dyssynchrony of circadian rhythms is associated with various disorders, including cardiovascular and metabolic diseases. The cell autonomous molecular clock maintains circadian control; however, environmental factors that may cause circadian dyssynchrony either within or between organ systems are poorly understood. Our laboratory recently reported that the endothelin (ET-1) B (ETB) receptor functions to facilitate Na+ excretion in a time of day-dependent manner. Therefore, the present study was designed to determine whether high salt (HS) intake leads to circadian dyssynchrony within the kidney and whether the renal endothelin system contributes to control of the renal molecular clock. We observed that HS feeding led to region-specific alterations in circadian clock components within the kidney. For instance, HS caused a significant 5.5-h phase delay in the peak expression of Bmal1 and suppressed Cry1 and Per2 expression in the renal inner medulla, but not the renal cortex, of control rats. The phase delay in Bmal1 expression appears to be mediated by ET-1 because this phenomenon was not observed in the ETB-deficient rat. In cultured inner medullary collecting duct cells, ET-1 suppressed Bmal1 mRNA expression. Furthermore, Bmal1 knockdown in these cells reduced epithelial Na+ channel expression. These data reveal that HS feeding leads to intrarenal circadian dyssynchrony mediated, in part, through activation of ETB receptors within the renal inner medulla.


Assuntos
Proteínas CLOCK/metabolismo , Rim/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Sódio na Dieta/metabolismo , Animais , Ritmo Circadiano/fisiologia , Endotelinas/metabolismo , Comportamento Alimentar/fisiologia , Masculino , Proteínas Circadianas Period/metabolismo , Ratos
19.
Fish Shellfish Immunol ; 69: 211-217, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28860073

RESUMO

miR-92a, a well-documented oncogene, was previously found to be differentially expressed in diseased sea cucumber Apostichopus japonicus by high-throughput sequencing. In this study, we identified Aj14-3-3ζ as a novel target of miR-92a in this species and investigated their regulatory roles in vivo. The negative expression profiles between miR-92a and Aj14-3-3ζ protein were detected in both LPS-exposed primary coelomocytes and Vibrio splendidus-challenged sea cucumbers. Over-expression of miR-92a by injection of miR-92a agomir significantly depressed the mRNA and protein expression of Aj14-3-3ζ and promoted coelomocytes apoptosis with 5.04-fold increase in vivo, which was consistent with those from siRNA-mediated Aj14-3-3ζ knockdown assay. In contrast, miR-92a antagomir significantly elevated the mRNA and protein expression of Aj14-3-3ζ and decreased coelomocytes apoptosis. Taken together, our result confirmed that miR-92a is involved in apoptotic signaling pathway regulation perhaps via targeting Aj14-3-3ζ in sea cucumbers, which will enhance our understanding of miR-92a regulatory roles in sea cucumber pathogenesis.


Assuntos
Proteínas 14-3-3/genética , Apoptose/genética , Regulação da Expressão Gênica , Imunidade Inata , MicroRNAs/genética , Stichopus/genética , Stichopus/imunologia , Animais , Transdução de Sinais , Transcriptoma
20.
Am J Physiol Regul Integr Comp Physiol ; 313(4): R425-R437, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28701323

RESUMO

Hypertension is a prevalent pathology that increases risk for numerous cardiovascular diseases. Because the etiology of hypertension varies across patients, specific and effective therapeutic approaches are needed. The role of renal sympathetic nerves is established in numerous forms of hypertension, but their contribution to salt sensitivity and interaction with factors such as endothelin-1 are poorly understood. Rats deficient of functional ETB receptors (ETB-def) on all tissues except sympathetic nerves are hypertensive and exhibit salt-sensitive increases in blood pressure. We hypothesized that renal sympathetic nerves contribute to hypertension and salt sensitivity in ETB-def rats. The hypothesis was tested through bilateral renal sympathetic nerve denervation and measuring blood pressure during normal salt (0.49% NaCl) and high-salt (4.0% NaCl) diets. Denervation reduced mean arterial pressure in ETB-def rats compared with sham-operated controls by 12 ± 3 (SE) mmHg; however, denervation did not affect the increase in blood pressure after 2 wk of high-salt diet (+19 ± 3 vs. +16 ± 3 mmHg relative to normal salt diet; denervated vs. sham, respectively). Denervation reduced cardiac sympathetic-to-parasympathetic tone [low frequency-high frequency (LF/HF)] during normal salt diet and vasomotor LF/HF tone during high-salt diet in ETB-def rats. We conclude that the renal sympathetic nerves contribute to the hypertension but not to salt sensitivity of ETB-def rats.


Assuntos
Pressão Sanguínea/fisiologia , Denervação , Hipertensão/genética , Hipertensão/cirurgia , Rim/inervação , Receptor de Endotelina B/genética , Cloreto de Sódio na Dieta/administração & dosagem , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/fisiopatologia , Rim/fisiopatologia , Rim/cirurgia , Sistema Nervoso Parassimpático/fisiopatologia , Ratos , Ratos Transgênicos , Sistema Nervoso Simpático/fisiopatologia
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