Beneficial Effects of Isoflavones in the Kidney of Obese Rats Are Mediated by PPAR-Gamma Expression.

Several studies have demonstrated an important association between altered lipid metabolism and the development of kidney injury because of a high-fat diet. Fructose is also closely associated with renal injury. We opted for a combination of fructose and saturated fats in a diet (DH) that is a model known to induce renal damage in order to evaluate whether soy isoflavones could have promising use in the treatment of renal alterations. After two months of ingestion, there was an expansion of visceral fat, which was associated with long-term metabolic disorders, such as sustained hyperglycemia, insulin resistance, polyuria, dyslipidemia, and hypertension. Additionally, we found a decrease in renal blood flow and an increase in renal vascular resistance. Biochemical markers of chronic kidney disease were detected; there was an infiltration of inflammatory cells with an elevated expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß), the activation of the renin-angiotensin system, and oxidative/nitrosative stress. Notably, in rats exposed to the DH diet for 120 days, the concomitant treatment with isoflavones after 60 days was able to revert metabolic parameters, renal alterations, and oxidative/nitrosative stress. The beneficial effects of isoflavones in the kidney of the obese rats were found to be mediated by expression of peroxisome proliferator-activated receptor gamma (PPAR-γ).

Proteção funcional da enzima heme-oxigenase-1 na lesão renal aguda isquêmica e tóxica / Functional protection of heme-oxygenase-1 enzyme in ischemic and toxic acute kidney injury / Protección funcional de la enzima heme-oxigenasa-1 en la lesión renal aguda isquémica y tóxica

Objetivos: Verificar a proteção funcional da heme-oxigenase (HO-1), por meio do uso do seu indutor (Hemin) e seu inibidor químico (protoporfirina de zinco-ZnPP) na lesão renal aguda isquêmica e tóxica pela Polimixina B (PmxB) em ratos. Material: Foram utilizados ratos Wistar, adultos e machos divididos em 8 grupos: SHAM (controle), Isquemia (Isq), Isq+Hemin (indutor de HO-1), Isq+ZnPP (inibidor de HO-1), SALINA (controle), Polimixina B (PmxB), PmxB+Hemin, PmxB+ZnPP. Métodos: Jaffé (clearance de creatinina, Clcr) e FOX-2 (peróxidos urinários). Resultados: A isquemia (30´) dos pedículos reais e a administração de PmxB reduziu o Clcr com manutenção do fluxo urinário. Os peróxidos urinários se elevaram em ambas as lesões. A administração do Indutor de HO-1 determinou melhora da função renal e redução dos níveis de peróxidos urinários. Conclusão: Os resultados deste estudo demonstraram que a isquemia e a PmxB induzem LRA oxidativa. O indutor de HO-1 atenuou a lesão em ambos os modelos por atenuação do mecanismo redox.

Objectives: To investigate the functional protection of heme-oxygenase-1 enzyme (HO-1) when using its inducer (Hemin) and inhibitor (zinc protoporphyrin-ZnPP) in ischemic and toxic acute kidney injury by Polymixin B in mice. Materials: Adult male Wistar mice divided into 8 groups were used: SHAM (control), Ischemic (Isq), Isq+Hemin (Inducer of H0-1), Isq+ZnPP (inhibitor of H0-1), SALINA (control), Polimyxin B (PmxB), PmxB+Hemin, PmxB+ZnPP. Method: Analysis consists of Jaffé (creatinine clearance [crCl]) and FOX-2 (urinary peroxides [UP]). Results: Thirty minutes renal ischemia and its treatment with PmxB reduced the crCl and maintained urinary output. Urinary peroxide levels increased in both injuries. The administration of the inducer of H0-1 resulted in improvement in renal function and reduction in the levels of urinary peroxide. Conclusions: Findings indicated that ischemia and PmxB induce LAR (acute kidney injury [AKI]) by elevating the levels of urinary peroxide. The HO-1 inducer ameliorated the injury in both animal models through redox mechanism.

Objetivos: Verificar la protección funcional de la heme-oxigenasa (HO-1), por medio del uso de su inductor (Hemin) y su inhibidor químico (protoporfirina de zinc-ZnPP) en la lesión renal aguda isquémica y tóxica producida por la Polimixina B (PmxB) en ratas. Material: Fueron utilizadas ratas Wistar, adultas y machos divididos en 8 grupos: SHAM (control), Isquemia (Isq), Isq+Hemin (indutor de HO-1), Isq+ZnPP (inibidor de HO-1), SALINA (control), Polimixina B (PmxB), PmxB+Hemin, PmxB+ZnPP. Métodos: Jaffé (clearance de creatinina, Clcr) y FOX-2 (peróxidos urinarios). Resultados: La isquemia (30´) de los pedículos reales y la administración de PmxB redujo el Clcr con manutención del flujo urinario. Los peróxidos urinarios se elevaron en ambas lesiones. La administración del Inductor de HO-1 determinó mejora de la función renal y reducción de los niveles de peróxidos urinarios. Conclusión: Los resultados de este estudio demuestran que la isquemia y la PmxB inducen AKL por la elevación de los peróxidos urinarios. El inductor de HO-1 atenuó la lesión en ambos modelos por atenuación del mecanismo redox.

Função renal de pacientes de unidade de terapia intensiva: creatinina plasmática e proteína carreadora do retinol urinário / Renal function of intensive care unit patients: plasma creatinine and urinary retinol-binding protein

OBJETIVOS: A avaliação precoce da disfunção renal usando marcadores usuais não supre uma indicação quer da sensitividade e da especificidade da disfunção renal de pacientes críticos. Seriam desejáveis marcadores mais específicos e sensíveis para a detecção precoce de um processo fisiopatológico renal em fase inicial. A proteína carreadora do retinol urinário poderia ser um método alternativo para avaliação precoce da função renal destes pacientes. MÉTODOS: O estudo acompanhou 100 pacientes em terapia intensiva e avaliou suas variáveis clinicas e laboratoriais, incluindo a dosagem de creatinina plasmática e proteina carreadora do retinol urinário e as variáveis demográficas. RESULTADOS: A amostra foi caracterizada por pacientes geriátricos (63,4±15,6 anos), homens (68 por cento), sendo 53 por cento cirúrgicos. Análise estatística mostrou associação entre creatinina plasmática e as seguintes variáveis: gênero (p=0,026), idade (p=0,038), uso de medicação vasoativa (p=0,003), proteinúria (p=0,025), escore Acute Physiological Chronic Health Evaluation (APACHE) II (p=0,000), uréia (p=0,000), potássio (p=0,003) clearance de creatinina estimado (p=0,000). A proteína carreadora do retinol urinário correlacionava-se com outras variáveis: peso usa de ventilação invasiva (p=0,000), uso de medicamentos antinfamatórios não-esteróides (p=0,018), uso de medicação vasoativa (p=0,021), temperatura alta (>37,5ºC) (p=0,005), proteinúria (p=0,000), bilirubinúria (p=0,004), fluxo urinário (p=0,019), pressão diastólica mínima (p=0,032), pressão sistólica mínima (p=0,029), APACHE II (p=0.000), creatinina (p=0,001), uréia (p=0,001) e clearance de creatinina estimado (p=0,000). A proteína carreadora do retinol urinário também tende a ser associada com doença renal anterior, vasculopatias e neoplasias. Na análise univariada, a fração de excreção de sódio se correlacionou com creatinina plasmática e proteina carreadora do retinol urinário. CONCLUSÃO: A proteina...

OBJECTIVES: The early assessment of renal dysfunction using common markers does not provide either a sensitive or specific indication of renal dysfunction in critically ill patients. More specific and sensitive markers are desirable for the early detection of an initial renal pathophysiological process. Urinary retinol-binding protein could be an alternative method to early evaluation of renal function in these patients. METHODS: This study followed-up 100 critical care patients and assessed their clinical and laboratory variables, including plasma creatinine and urinary retinol-binding ratio, and demographic variables. RESULTS: The sample was characterized by geriatric (63.4±15.6 years), male (68 percent), being 53 percent surgical patients. Statistical analysis showed association between plasma creatinine and the following variables: gender (p-0.026), age (p-0.038), use of vasoactive drugs (p-0.003), proteinuria (p-0.025), Acute Physiological Chronic Health Evaluation (APACHE) II score (p-0.000), urea (p-0.000), potassium (p-0.003) and estimated creatinine clearance (p-0.000). Urinary retinol-binding protein was correlated with more variables: weight, use of invasive ventilation (p-0.000), use of nonsteroidal antiinflammatory drugs (p-0.018), use of vasoactive drugs (p-0.021), high temperature (>37.5ºC) (p-0.005), proteinuria (p-0.000), bilirubinuria (p-0.004), urinary flow (p-0.019), minimal diastolic pressure (p-0.032), minimal systolic pressure (p-0.029), APACHE II (p-0.000), creatinine (p-0.001), urea (p-0.001), estimated creatinine clearance (p-0.000). Urinary retinol-binding protein also tended to associate with previous renal disease, vasculopathy and neoplasm. Sodium excretion fraction correlated with plasma creatinine and urinary retinol-binding protein in univariate analysis. CONCLUSIONS: Urinary retinol-binding protein might be considered in clinical practice as a better marker regarding diagnostic performance in patients...

Renal function of intensive care unit patients: plasma creatinine and urinary retinol-binding protein. / Função renal de pacientes de unidade de terapia intensiva: creatinina plasmática e proteína carreadora do retinol urinário.

OBJECTIVES: The early assessment of renal dysfunction using common markers does not provide either a sensitive or specific indication of renal dysfunction in critically ill patients. More specific and sensitive markers are desirable for the early detection of an initial renal pathophysiological process. Urinary retinol-binding protein could be an alternative method to early evaluation of renal function in these patients. METHODS: This study followed-up 100 critical care patients and assessed their clinical and laboratory variables, including plasma creatinine and urinary retinol-binding ratio, and demographic variables. RESULTS: The sample was characterized by geriatric (63.4±15.6 years), male (68%), being 53% surgical patients. Statistical analysis showed association between plasma creatinine and the following variables: gender (p-0.026), age (p-0.038), use of vasoactive drugs (p-0.003), proteinuria (p-0.025), Acute Physiological Chronic Health Evaluation (APACHE) II score (p-0.000), urea (p-0.000), potassium (p-0.003) and estimated creatinine clearance (p-0.000). Urinary retinol-binding protein was correlated with more variables: weight, use of invasive ventilation (p-0.000), use of nonsteroidal antiinflammatory drugs (p-0.018), use of vasoactive drugs (p-0.021), high temperature (>37.5ºC) (p-0.005), proteinuria (p-0.000), bilirubinuria (p-0.004), urinary flow (p-0.019), minimal diastolic pressure (p-0.032), minimal systolic pressure (p-0.029), APACHE II (p-0.000), creatinine (p-0.001), urea (p-0.001), estimated creatinine clearance (p-0.000). Urinary retinol-binding protein also tended to associate with previous renal disease, vasculopathy and neoplasm. Sodium excretion fraction correlated with plasma creatinine and urinary retinol-binding protein in univariate analysis. CONCLUSIONS: Urinary retinol-binding protein might be considered in clinical practice as a better marker regarding diagnostic performance in patients at risk of developing acute kidney injury, when compared with other markers routinely used. Moreover, urinary retinol-binding protein has other features of a good diagnostic test - it is a practical and non-invasive method.

A enzima heme oxigenase-1 na lesão renal aguda oxidativa pela polimixina B / The heme oxygenase-1 enzyme in oxidative acute kidney injury by polymyxin B

A Lesão Renal Aguda (LRA) tóxica se caracteriza por insulto tubular direto liberando espécies reativas de oxigênio (EROs) e estimulando processos pró-inflamatórios. Neste estudo foram investigadas a toxicidade do Sulfato de Polimixina B (PmxB), antibiótico catiônico usado para o tratamento de infecções por germes gram-negativos e a participação da enzima Heme Oxigenase-1 (HO-1), que tem efeito anti-apoptótico, antiinflamatório e outros. Foram utilizados ratos Wistar, adultos, machos, pesando entre 250-300g. Os animais foram distribuídos nos grupos: Salina (controle, animais que receberam 3ml/Kg de NaCI 0,9% intraperitoneal (i.p.), uma vez ao dia, 5 dias); PmxB(animais que receberam PmxB 40.000U/kg/dia, i.p., uma vez ao dia, 5 dias); Hemin (indutor da HO-1, 1mg/100g, i.p., uma vez ao dia 5 dias); Protoporfirina de Zinco (ZnPP) (inibidor da HO-1, 50 umol/Kg, i.p., uma vez ao dia, 5 dias); PmxB+Hemin; PmxB+ZnPP; PmxB+Hemin+ZnPP. Foram avaliados a função renal (FR) (clearance de creatinina, método de Jaffé), a excreção de peróxidos urinários (PU, FOX-2); TBARS urinários; tióis no tecido renal, atividade da catalse (AC) e foi realizada análise histológica no tecido renal. Os resultados mostraram que a PmxB induziu redução da FR com elevação de PU e TBARS, acompanhados por redução de AC e tióis: O tratamento com indutor da HO-1 reverteu a lesão pela PmxB, com melhora da FR e dos parâmetros de peroxidação. A associação do PmxB com o inibidor ZnPP demonstrou aumento daárea intersticial relativa (AIR) no tecido renal com achatamento das células tubulares e pontos de necrose no córtex renal. Os resultados diferenciados de FR e peroxidação lipídica, nas técnicas de mensuração utilizadas, confirmaram a participação da heme oxigenase como antioxidante desse modelo de toxicidade renal.

Toxic Acute Kidney Injury (AKI) consists on direct injury in the renal tubules liberating reactive oxygen species (ROS) and estimulating inflamatory processes. In this experimental study it was investigated the toxicity of Polymyxin B Sulfate (PmxB), which is a cationic antibiotic used to treat gram-negative infections and the role of the heme oxygenase enzyme (HO-1), with anti-apoptotic and anti-inflamatory effects, in this injury. Adult male Wistar rats, weighing 250-300g were used. The animals were divided into the following groups: Saline (contro, animals that received 3ml/Kg of NaCI 0,9% intraperitoneal (i.p.), once a day, 5 days); PmxB (animals that received PmxB 40.000U/kg/dia, i.p., once a day, 5 days); Hemin (HO-1 inducer, 1mg/100g, i.p., once a day, 5 days); Zinc protoporphyrin (ZnPP) (HO-1 inhibitor, 50 umol/Kg, i.p., once a day, 5 days); PmxB+Hemin; PmxB+ZnPP; PmxB+Hemin+ZnPP. Renal Function (RFf) (creatinine clearance, Jaffé method), urinary peroxides (UP, FOX-2), urinary TBARS, thiols in the renal tissue, activity of catalasse enzyme (CA) and histology of renal tissue were performed. The results showed that PmxB reduced RF with increment in the UP and TBARS associated to the reduction in the CA and thiols. The HO-1 ameliorated these paramethers. The association PmxB with ZnPP increased relative intersticial area (RIA) of renal tissue with acute tubule necrosis in the renal cortex. The obtained data on RF and lipid peroxidation, with the methods used inthe study, confirmed the antioxidant role of the heme oxygenase in this model of renal injury.