CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Acute renal failure (AFR) is one of the most complicated and critical events during the septic event, manifesting by production of reactive oxygen species (ROS), glomerular and tubular disorders, which contributes to worsening the prognosis and decreases in survival. [6]-gingerol and [10]-gingerol phenolic compounds are bioactive substances from ginger (Zingiber officinale Rosc.). Such compounds own protective potential effect on renoprotection due to their antioxidant and anti-inflammatory properties. This study investigated the modulatory effects of the [6]- and [10]-gingerol compounds on the renal damage triggered by cecal ligation and puncture (CLP)-induced ARF. Male Wistar rats (180-210 g) were divided into 6 groups (protocol. 45/14). The control groups (Sham) were induced to false surgery and subsequently treated with 2% Tween-80, [6]- or [10]-gingerol (25 mg/kg); AFR groups were induced by CLP process and subsequently trated with 2% tween-80, [6]- or [10]-gingerol (25 mg/kg, i.p.). The treatments were performed 2 hours before and 12 and 24 hours after induction. The biochemical parameters indicative of renal and tubular function, oxidative profile, antioxidant activity and gene expression of pro-inflammatory mediators by RT-qPCR we evaluated. In addition, the metabolomic profile by Nuclear Magnetic Resonance (NMR) assays and histological analysis were also performed. The polymicrobial infection altered considerably parameters related to renal function, decreasing CLCR (0.4Â0.1 mL/min), FU (0.008Â0.001mL/min) with reduction of the GSH content (13.55Â1.3 μg/mg/prot.). Indeed, had an increased of the BUN (62.1Â2.1mg/dL), PU:CUR (46.6Â7.4 mg/dL), the LDH activity (383.7Â80.2 U/L), the FENa (1.5Â0.3%), renal MDA (1.725Âg/mg prot.) and nitrite (61.5Â9.5 nM/g prot.). On the other hand, TNF-α levels, and IL-1β were increased (1.4Â0.1 and 5.5Â0.8 relative expression, respectively), triggering kidney failure and decreasing the survival of animals. The treatment with both compounds [6]-gingerol and [10]-gingerol (25mg/kg) exerted protection on renal injury. Improved the CLCR (1.2Â0.2 mL/min and 1.0Â0.07 mL/min, [6]- and [10]-gingerol, respectively) and FU (0.01Â0,001mL/min, 0.010Â0.001mL/min, [6]- and [10]-gingerol, respectively) with increased GSH activity (26.22Â2.0 Âg/mg prot. and 24.06Â3.5 Âg/mg prot., [6]- and [10]-gingerol, respectively). In addition, the BUN (46.83Â2.7mg/dL, [6]-gingerol), PU:CUR (22.95Â7.18mg/dL and 21.58Â4.29 mg/dL [6]- and [10]-gingerol, respectively), the LDH activity (212.7Â30.85 mg/dL and 236.3Â43.8mg/dL, [6]- and [10]-gingerol, respectively), FENa (0.6Â0.1% 0.58Â0.09% e [6]- and [10]-gingerol, respectively), renal MDA (0.7462Â0.16 mg de prot., [6]-gingerol) and nitrite (36.6Â4.1 nM/g prot. and 38.98Â7.9 nM/g prot. [6]- and [10]-gingerol, respectively) were all decreased. Besides the inhibition of TNF-α transcription (0.865 e 1.030, [6]- and [10]-gingerol, respectively) and IL-1β (3.330 e 1.790, [6]- and [10]-gingerol, respectively), providing protection on kidney function and increased survival of CLP animals. In addition, the specific injury to kidney cells was confirmed by the expressive values of Kidney Injury Molecule-1 (KIM-1) in septic animals, which were blocked by compounds [6]- and [10]-gingerol. Improvement in renal morphology was correlated with increased survival of CLP animals after [6]- and [10]-gingerol treatment. The principal component analysis (PCA) reported phenotypic changed in the metabolic profile by metabolite discrimination among the sham, CLP and CLP groups treated with [6]- or [10]-gingerol. The 1H NMR approach indicated increased in creatine, allantoin, dimethylglycine (DMG) and taurine in the CLP group (P<0.05). In addition, the dimethylamine (DMA) and dimethyl sulfone (DMS) metabolites were more present in samples of CLP animals treated with [6]- and [10]-gingerol. The present study indicates that [6]- and [10]-gingerol has a nephroprotective effect on dysfunction, oxidative stress and renal proinflammatory process in polymicrobial sepsis. In addition to designating quantified metabolites in the urine as biomarkers correlated with the pathophysiology of sepsis with manifestation of renal failure. / A lesÃo renal aguda (LRA) à uma das manifestaÃÃes mais crÃticas durante o evento sÃptico, manifestando-se por produÃÃo de espÃcies reativas de oxigÃnio, alteraÃÃes glomerulares e tubulares, que contribuem para a piora do prognÃstico e diminuiÃÃo da sobrevida. Os compostos fenÃlicos [6]-gingerol e [10]-gingerol sÃo substÃncias bioativas do gengibre (Zingiber officinale Roscoe) que por meio de suas propriedades antioxidantes, antiflamatÃrias e metabÃlicas possuem um grande potencial para a renoproteÃÃo. O presente estudo investigou os efeitos moduladores dos compostos [6]- e [10]-gingerol diante ao dano renal desencadeado pelo modelo polimicrobiano cecal ligation and puncture (CLP) de sepse. Foram utilizados ratos Wistar (180-210 g) divididos em 6 grupos (protocol. 45/14). Os grupos controles Sham [grupos: I., II. e III.] foram induzidos à falsa cirurgia e subsequentemente tratados com tween-80 2%, com [6]-gingeol ou [10]-gingerol (25 mg/kg); grupos induzidos LRA [grupos: IV., V. e VII.] por meio do processo cirugico CLP e subsequentemente tratados com tween-80 2%, [6]-, ou [10]-gingerol (25 mg/kg). Os tratamentos foram realizados 2 horas prà e, por 12 e 24 apÃs induÃÃo. Foram avaliados os parÃmetros bioquÃmicos indicativos de funÃÃo renal, funÃÃo tubular, perfil oxidativo, atividade antioxidante e a transcriÃÃo gÃnica de mediadores prÃ-inflamatÃrios atravÃs de RT-PCR, anÃlise histopatolÃgica e taxa de sobrevida, alÃm do perfil metabolÃmico por meio de ensaios por ResonÃncia MagnÃtica Nuclear (RMN) de 1H. A infecÃÃo polimicrobiana modificou de forma considerÃvel os parÃmetros relacionados à funÃÃo renal. Observou-se uma diminuiÃÃo do clearance de creatinina (CLCR) (0,4Â0,1 mL/min), do fluxo urinÃrio (FU) (0,0086Â0,001mL/min) e do conteÃdo de GSH (13,5Â1,3 μg/mg prot.). Por outro lado, houve um aumento nos valores de ureia (62,1Â2,1mg/dL), da razÃo proteÃna urinÃria: creatina urinÃria [PU:CRU (46,6Â7,4 mg/dL)], da atividade da LDH (383,7Â8 U/L), da FENa (1,5Â0,3%), de MDA renal (1,72Â0,37 Âg/mg prot.) e nitrito (61,5Â9,5 nM/g prot.), alÃm da elevaÃÃo de TNF-α (1,380 relativa transcriÃÃo) e IL-1β (5,87 relativa transcriÃÃo) no tecido renal. Estas alteraÃÃes desencadearam falha renal e reduÃÃo da sobrevida dos animais (P<0,05). O tratamento com ambos os compostos [6]-gingerol ou [10]-gingerol na dose de 25mg/kg atenuou a injuria renal, melhorando consideravelmente os parÃmetros anteriores. Evidenciou-se uma conservaÃÃo do CLCR (1,2Â0,2 mL/min e 1,0Â0,07 mL/min, [6]- e [10]-gingerol, respectivamente), do FU (0,01Â0,001mL/min; 0,010Â0,001mL/min, [6]- e [10]-gingerol, respectivamente) com melhora da atividade da GSH (26,2Â2,0 Âg/mg prot. e 24,06Â3,5 Âg/mg prot., [6]- e [10]-gingerol, respectivamente). AlÃm da diminuiÃÃo dos nÃveis de ureia (46,83Â2,7mg/dL, [6]-gingerol), da PU:CRU (22,9Â7,18mg dL e 21,58Â4,2mg/dL, [6]- e [10]-gingerol, respectivamente), da atividade da LDH (212,7Â30,8 U/L e 236,3Â43,8 U/L [6]- e [10]-gingerol, respectivamente), da FENa (0,6Â0,1% e 0,58Â0,09%, [6]- e [10]-gingerol, respectivamente), dos nÃveis de MDA renal (0,74Â0,16 Âg/mg prot., [6]-gingerol) e de nitrito (36,65Â4,1 nM/g prot. e 38,98Â7,952 nM/g/prot., [6]- e [10]-gingerol, respectivamente). O processo inflamatÃrio foi atenuado pelas reduÃÃes da transcriÃÃo gÃnica de TNF-α (0,865 e 1,030; [6]- e [10]-gingerol, respectivamente), de IL-1β (3,330 e 1,790 relativas transcriÃÃes, [6]- e [10]-gingerol, respectivamente). Em adiÃÃo, a injuria especifica as cÃlulas renais foi confirmada pelos valores expressivos de Kidney Injury Molecule-1 (KIM-1) nos rins de animais CLP, que foram bloqueados pelos fenois [6]- e [10]-gingerol e assim, demonstrando proteÃÃo da funÃÃo renal e aumentando a sobrevida dos animais. A exploraÃÃo por principal component analysis (PCA) reportou alteraÃÃes fenotÃpicas no perfil metabolÃlico por discriminaÃÃo de metabÃlitos entre os grupos sham, CLP e CLP tratados com [6]- ou [10]-gingerol. A abordagem por RMN de 1H reportou aumentos de creatina, alantoÃna, dimetilglicina (DMG) e taurina nas urinas do grupo CLP (P<0,05). AlÃm disso, os metabÃlitos de dimetilamina (DMA) e dimetil sulfona (DMS) estiveram mais presente em amostras de animais CLP tratados com [6]- e [10]-gingerol. O presente estudo indica que o [6]- e [10]-gingerol possui efeito nefroprotetor diante a disfunÃÃo, o estresse oxidativo e processo prÃ-inflamatÃrio renal na sepse polimicrobiana. AlÃm de designar metabÃlitos quantificados na urina como biomarcadores correlacionados com a fisiopatologia da sepse com manifestaÃÃo de falha renal.
| Identifer | oai:union.ndltd.org:IBICT/oai:www.teses.ufc.br:12000 |
| Date | 10 February 2017 |
| Creators | Francisco Adelvane de Paulo Rodrigues |
| Contributors | Alexandre Havt BindÃ, Aldo Ãngelo Moreira Lima, ManassÃs Claudino Fonteles, ClÃudia Ferreira Santos, Taina Veras de Sandes Freitas |
| Publisher | Universidade Federal do CearÃ, Programa de PÃs-GraduaÃÃo em Farmacologia, UFC, BR |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da UFC, instname:Universidade Federal do Ceará, instacron:UFC |
| Rights | info:eu-repo/semantics/openAccess |
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