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There are several Amazonian plant species with potential pharmacological validation for the treatment of acute kidney injury, a condition in which the kidneys are unable to adequately filter the blood, resulting in the accumulation of toxins and waste in the body. Scientific production on plant compounds capable of preventing or attenuating acute kidney injury-caused by several factors, including ischemia, toxins, and inflammation-has shown promising results in animal models of acute kidney injury and some preliminary studies in humans. Despite the popular use of Amazonian plant species for kidney disorders, further pharmacological studies are needed to identify active compounds and subsequently conduct more complex preclinical trials. This article is a brief review of phytocompounds with potential nephroprotective effects against acute kidney injury (AKI). The classes of Amazonian plant compounds with significant biological activity most evident in the consulted literature were alkaloids, flavonoids, tannins, steroids, and terpenoids. An expressive phytochemical and pharmacological relevance of the studied species was identified, although with insufficiently explored potential, mainly in the face of AKI, a clinical condition with high morbidity and mortality.
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Injúria Renal Aguda , Animais , Humanos , Injúria Renal Aguda/tratamento farmacológico , Rim , Flavonoides , Inflamação , Modelos AnimaisRESUMO
AIMS: Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, has received extensive attention as a natural activator of the Nrf2/Keap1 cytoprotective pathway. In this review, a meta-analysis and systematic review of the renoprotective effects of SFN were performed in various preclinical models of kidney diseases. MAIN METHODS: The primary outcome was the impact of SFN on renal function biomarkers (uremia, creatininemia, proteinuria or creatinine clearance) and secondary outcomes were kidney lesion histological indices/kidney injury molecular biomarkers. The effects of SFN were evaluated according to the standardized mean differences (SMDs). A random-effects model was applied to estimate the overall summary effect. KEY FINDINGS: Twenty-five articles (out of 209 studies) were selected from the literature. SFN administration significantly increased creatinine clearance (SMD +1.88 95 % CI: [1.09; 2.68], P < 0.0001, I2 = 0 %) and decreased the plasma creatinine (SMD -1.24, [-1.59; -0.88], P < 0.0001, I2 = 36.0 %) and urea (SMD -3.22 [-4.42, -2.01], P < 0.0001, I2 = 72.4 %) levels. SFN administration (median dose: 2.5 mg/kg, median duration: 3 weeks) significantly decreased urinary protein excretion (SMD -2.20 [-2.68; -1.73], P < 0.0001, I2 = 34.1 %). It further improved two kidney lesion histological indices namely kidney fibrosis (SMD -3.08 [-4.53; -1.63], P < 0.0001, I2 = 73.7 %) and glomerulosclerosis (SMD -2.24 [-2.96; -1.53], P < 0.0001, I2 = 9.7 %) and decreased kidney injury molecular biomarkers (SMD -1.51 [-2.00; -1.02], P < 0.0001, I2 = 0 %). SIGNIFICANCE: These findings provide new insights concerning preclinical strategies for treating kidney disease or kidney failure with SFN supplements and should stimulate interest in clinical evaluations of SFN in patients with kidney disease.
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Nefropatias , Fator 2 Relacionado a NF-E2 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Creatinina , Fator 2 Relacionado a NF-E2/metabolismo , Nefropatias/tratamento farmacológico , Isotiocianatos/farmacologia , Isotiocianatos/uso terapêutico , Biomarcadores/metabolismoRESUMO
Contexto: el ácido úrico es el producto final de la degradación de las purinas en los primates, en condiciones normales es un agente antioxidante endógeno y participa en varias vías fisiológicas, sin embargo, cuando los niveles séricos de urato se incrementan, estos participan en el desarrollo de diversas enfermedades. Desde el siglo XIX se conoce de la asociación entre hiperuricemia y daño renal, aunque ninguna guía de manejo recomienda el uso de fármacos hipouricemiantes en pacientes asintomáticos, en algunos casos especiales, el manejo farmacológico beneficiará a pacientes con hiperuricemia, brindando protección al riñón y disminuyendo el riesgo de desarrollar enfermedad renal terminal. Objetivo: describir la relación entre hiperuricemia y daño renal, y analizar los casos en los que el manejo de esta condición con medicamentos resultará en un beneficio para el riñón de los pacientes. Metodología: revisión de la literatura sobre la participación de la hiperuricemia en el daño renal y análisis de los artículos revisados. Resultados: el manejo de la hiperuricemia asintomática puede proteger el riñón en algunas situaciones específicas. Conclusiones: hay situaciones específicas para la disminución de los niveles séricos de ácido úrico.
Background: Uric acid is the end product of purine degradation in primates, under normal conditions it is an endogenous antioxidant agent and participates in several physiological pathways. However, when serum urate levels are increased, they participate in the development of various diseases. Since the nineteenth century, the association between hyperuricemia and kidney damage has been known. Although no management guideline recommends the use of hypouricemic drugs in asymptomatic patients, in some special cases pharmacological management will benefit patients with hyperuricemia, providing protection to the kidney and decreasing the risk of developing end-stage renal disease. Purpose: To describe the relationship between hyperuricemia and kidney damage, and to analyze the cases in which the management of this condition with medications will result in a benefit for the kidney of patients. Methodology: Review of the literature on the involvement of hyperuricemia in kidney damage, analysis of the reviewed articles. Results: Management of asymptomatic hyperuricemia may protect the kidney in some specific situations. Conclusions: There are specific situations for the decrease of serum uric acid levels.
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Nephrotoxicity is an important adverse effect of oxidative stress induced by hexavalent chromium [Cr(VI)]. The effect of ellagic acid, a dietary polyphenolic compound with potent antioxidant activity, was investigated in Cr(VI)-induced kidney injury. Six groups of male Wistar rats were treated intragastrically with vehicle or ellagic acid (15 and 30 mg/kg) for 10 days. On day 10, rats received saline or Cr(VI) (K2Cr2O7 15 mg/kg) subcutaneously. Cr(VI) significantly increased kidney weight, affected kidney function assessed by biomarkers in blood and urine (protein, creatinine and urea nitrogen), caused histological changes (tubular injury and glomerular capillary tuft damage), increased markers of oxidative stress and reduced the activity of antioxidant enzymes. In addition, Cr(VI) altered mitochondrial ultrastructure, impaired mitochondrial respiration, increased lipid peroxidation, and inhibited the function of mitochondrial enzymes. Pretreatment with ellagic acid (30 mg/kg) attenuated all the aforementioned alterations. Furthermore, we explored whether ellagic acid might regulate the tumor necrosis factor-alpha (TNF-α)/receptor-interacting protein kinase 3 (RIPK3) pathway, reducing Cr(VI)-induced tubular necrosis. Cr(VI) upregulated both TNF-α and RIPK3, but ellagic acid only decreased TNF-α levels, having no effect on RIPK3 content. Therefore, understanding the mechanisms through which Cr(VI) promotes necroptosis is crucial for future studies, in order to design strategies to mitigate kidney damage. In conclusion, ellagic acid attenuated Cr(VI)-induced renal alterations by preventing oxidative stress, supporting enzymatic activities, suppressing TNF-α, and preserving mitochondrial ultrastructure and function, most likely due to its antioxidant properties.
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Antioxidantes , Fator de Necrose Tumoral alfa , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Cromo/metabolismo , Cromo/toxicidade , Creatinina , Ácido Elágico/metabolismo , Ácido Elágico/farmacologia , Rim , Masculino , Mitocôndrias/metabolismo , Nitrogênio/metabolismo , Estresse Oxidativo , Proteínas Quinases/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Ureia/metabolismoRESUMO
Kidney diseases are expected to become the fifth leading cause of death by 2040. Several physiological failures classified as pre-, intra-, and post-renal factors induce kidney damage. Diabetes, liver pathologies, rhabdomyolysis, and intestinal microbiota have been identified as pre-renal factors, and lithiasis or blood clots in the ureters, prostate cancer, urethral obstructions, prostate elongation, and urinary tract infections are post-renal factors. Additionally, the nephrotoxicity of drugs has been highlighted as a crucial factor inducing kidney injuries. Due to the adverse effects of drugs, it is necessary to point to other alternatives to complement the treatment of these diseases, such as nephroprotective agents. Plants are a wide source of nephroprotective substances and can have beneficial effects in different levels of the physiological pathways which lead to kidney damage. In traditional medicines, plants are used as antioxidants, anti-inflammatories, diuretics, and anticancer agents, among other benefits. However, the mechanism of action of some plants empirically used remains unknown and scientific data are required to support their nephroprotective effects. The present work reviewed the plants with a beneficial effect on kidney diseases. The classification of nephroprotective plants according to the clinical definition of pre-renal, intrinsic, and post-renal factors is proposed to orient their use as complementary treatments.
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Cisplatin is an effective antineoplastic agent, but its use is limited by its nephrotoxicity caused by the oxidative stress in tubular epithelium of nephrons. On the other hand, regular exercise provides beneficial adaptations in different tissues and organs. As with many drugs, dosing is extremely important to get the beneficial effects of exercise. Thus, we aimed to investigate the influence of exercise intensity and frequency on cisplatin-induced (20 mg/kg) renal damage in mice. Forty male Swiss mice were divided into five experimental groups (n=8 per group): 1) sedentary; 2) low-intensity forced swimming, three times per week; 3) high-intensity forced swimming, three times per week; 4) low-intensity forced swimming, five times per week; and 5) high-intensity forced swimming, five times per week. Body composition, renal structure, functional indicators (plasma urea), lipid peroxidation, antioxidant enzyme activity, expression of genes related to antioxidant defense, and inflammatory and apoptotic pathways were evaluated. Comparisons considered exercise intensity and frequency. High lipid peroxidation was observed in the sedentary group compared with trained mice, regardless of exercise intensity and frequency. Groups that trained three times per week showed more benefits, as reduced tubular necrosis, plasma urea, expression of CASP3 and Rela (NFkB subunit-p65) genes, and increased total glutathione peroxidase activity. No significant difference in Nfe2l2 (Nrf2) gene expression was observed between groups. Eight weeks of regular exercise training promoted nephroprotection against cisplatin-mediated oxidative injury. Exercise frequency was critical for nephroprotection.
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Atrial natriuretic peptide belongs to the family of natriuretic peptides, a system with natriuretic, diuretic, and vasodilator effects that opposes to renin-angiotensin system. In addition to its classic actions, atrial natriuretic peptide exerts a nephroprotective effect given its antioxidant and anti-inflammatory properties, turning it as a beneficial agent against acute and chronic kidney diseases. This minireview describes the most relevant aspects of atrial natriuretic peptide in the kidney, including its renal synthesis, physiological actions through specific receptors, the importance of its metabolism, and its potential use in different pathological scenarios.
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The object of this study was to evaluate the relationship between oxidative damage induced by oxaliplatin (OXA) and the therapeutic potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) in kidney of mice. Mice received OXA (10 mg/kg) or vehicle intraperitoneally (days 0 and 2). Oral administration of 4-PSQ (1 mg/kg) or vehicle was performed on days 2 to 14. On day 15 the animals were euthanized and the kidneys and blood were collected. The effect of OXA and (or) 4-PSQ on urea, thiobarbituric acid reactive species, nonprotein thiol (NPSH), and protein carbonyl (PC) levels were investigated. Moreover, renal superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), δ-aminolevulinic acid dehydratase (δ-ALA-D), and Na+,K+ ATPase activities were evaluated. Our findings revealed an increase on urea levels and significant renal oxidative damage in OXA-induced mice. OXA exposure increased SOD, GPx, and GST activities and caused a reduction on NPSH levels and CAT and GR activities. Na+,K+ ATPase and δ-ALA-D activities were reduced by OXA. 4-PSQ decreased plasmatic urea levels and renal oxidative damage. SOD, GPx, CAT, GR, and Na+,K+ ATPase activities were restored by 4-PSQ. 4-PSQ may be a good prototype for the treatment of OXA-induced renal injury.
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Antioxidantes/farmacologia , Nefropatias/prevenção & controle , Oxaliplatina/efeitos adversos , Quinolinas/farmacologia , Animais , Antineoplásicos/toxicidade , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Superóxido Dismutase/metabolismoRESUMO
Gentamicin is an aminoglycoside antibiotic used to treat infections of various origins. In the last few decades, the constant use of gentamicin has resulted in increased bacterial resistance and nephrotoxicity in some cases. In this study, we examined the ability of Dioclea violacea lectin (DVL) in modulate the antimicrobial activity of gentamicin and reduce the nephrotoxicity induced by this drug. The minimum inhibitory concentration (MIC) obtained for DVL against all strains studied was not clinically relevant (MIC ≥ 1024 µg/mL). However, when DVL was combined with gentamicin, a significant increase in antibiotic action was observed against Staphylococcus aureus and Escherichia coli. DVL also reduced antibiotic tolerance in S. aureus during 10 days of continuous treatment. In addition, DVL presented a nephroprotective effect, reducing sodium excretion, N-Gal expression and urinary protein, that are important markers of glomerular and tubular injuries. Taken together, studies of inhibition of hemagglutinating activity, fluorescence spectroscopy and molecular docking revealed that gentamicin can interact with DVL via the carbohydrate recognition domain (CRD), suggesting that the results obtained in this study may be directly related to the interaction of DVL-gentamicin and with the ability of the lectin to interact with glycans present in the cells of the peritoneum.
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Antibacterianos/farmacologia , Dioclea/química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Gentamicinas/farmacologia , Rim/patologia , Lectinas de Plantas/farmacologia , Substâncias Protetoras/farmacologia , Animais , Antibacterianos/química , Bactérias/efeitos dos fármacos , Gentamicinas/química , Hemaglutinação/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/lesões , Rim/fisiopatologia , Masculino , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Lectinas de Plantas/química , Lectinas de Plantas/isolamento & purificação , Coelhos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de FluorescênciaRESUMO
Contrast-induced nephropathy (NIC) is directly related to increased morbidity and mortality, and its treatment and prevention might be achieved by the administration of antioxidant products. The juçara palmetto (Euterpe edulis Martius) has fruits rich in phenolic compounds, which are known for their antioxidant activity. This work aimed to evaluate the nephroprotective activity of E. edulis pulp in the NIC animal model. The collected fruits were pulped, their contents of polyphenols and anthocyanins were quantified, and their antioxidant activity were evaluated. The nephroprotective effects were determined based on iodine contrast induction and evaluated by biochemical and histological analyses. The results showed that E. edulis pulp was rich in polyphenols (811 ± 16.7 mg EAG/g) and anthocyanins (181.25 mg/100 g) and had very strong antioxidant activity, as demonstrated by the DPPH (2,2-diphenyl-1-picryl-hydrazyl) method, which revealed an antioxidant activity index (AAI) of 3.4, and the 2,29-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) method, which revealed an IC50 of 0.59 ± 0.03 mg/mL. In the in vivo experiments, E. edulis pulp tended to provide renal protection and reduce renal dysfunction and tubular morphological lesions in mice after the induction of NIC, and these effects were obtained through the antioxidant activities of the polyphenols in the pulp.
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Resumen: La diabetes mellitus 2 es una epidemia mundial, aunado a esto, la nefropatía diabética se ha convertido en la principal causa de insuficiencia renal en etapa terminal. En los pacientes con diabetes mellitus 2 existe sobreexpresión de los cotransportadores de glucosa ligados a la vía del sodio tipo 2 (SGLT2) que contribuyen al mantenimiento de la hiperglucemia. Por tanto, los inhibidores de este transportador representan un tratamiento innovador independiente de la acción de la insulina o la función de las células beta pancreáticas. En estudios recientes se ha demostrado que los iSGLT2 tienen efectos benéficos en la microvasculatura, en especial en la progresión de la nefropatía diabética. Este efecto no sólo se debe a la mejora del control glucémico, sino también a efectos directos en el riñón. Los iSGLT2, al inducir la glucosuria, revierten la glucotoxicidad renal. En estudios experimentales se ha observado que, además, se reduce la hiperfiltración, así como los marcadores inflamatorios y fibróticos. También se ha visto reducción del volumen circulante efectivo y aumento en la actividad de bloqueadores del sistema renina-angiotensina-aldosterona (bloqueadores RAA) circulantes, creando así un efecto nefroprotector.
Abstract: Type 2 diabetes mellitus 2 (DM2) is already a worldwide epidemic, in addition, diabetic nephropathy has become the leading cause of end-stage renal failure. In patients with DM2 there is an increased expression of the sodium-glucose cotransporters 2 (SGLT2) that contribute to the maintenance of hyperglycemia. Therefore, the inhibitors of this transporter represent an innovative therapy independent of the action of insulin or the function of pancreatic beta cells. Recent studies have shown that iSGLT2 have beneficial effects on microvasculature, especially in the progression of diabetic nephropathy. This effect is due not only to improved glycemic control but also to direct effects on the kidney. iSGLT2 induce glycosuria to reverse renal glucotoxicity. In experimental studies it has been observed that, in addition, hyper-filtration as well as inflammatory and fibrotic markers are reduced. There has also been a reduction in effective circulating volume and an increase in the activity of circulating renin-angiotensin-aldosterone system blockers (RAA blockers), thus creating a nephroprotective effect.
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Abstract In recent years, several new antidiabetic drugs have been developed, among which only two have demonstrated superiority in cardiovascular protection. They are liraglutide and empagliflozine, which belong, respectively, to GLP-1 RA and SGLT-2Í. These medications have also shown benefits in kidney protection. However, in a recent survey of the author among nephrologists in a large colombian city, it has been detected that most do not use these drugs. The greater resistance to the limitation in its use is due to the advanced stages of chronic kidney disease where they are contraindicated, but also to the anawareness of their potential benefits. In this regard, the nephrologists accepted they should learn more about these antidiabetic medicines, because the type of patient that is frequently attended in their consultation will undoubtly benefit, and considering they are obligated to handle the diabetic patient directly.
Resumen En los últimos años se han desarrollado nuevos fármacos antidiabéticos, entre los que sólo dos han demostrado superioridad en protección cardiovascular. Son liraglutida y empagliflozina, que pertenecen, respectivamente, a los grupos GLP-1 RA y SGLT-2Í. Estos medicamentos también han demostrado beneficios en nefroprotección. Sin embargo, en una reciente encuesta del autor entre nefrólogos, en una gran ciudad colombiana, se ha detectado que la mayoría no utilizan estos fármacos. La mayor resistencia a su uso se debe a consideraciones sobre su restricción en etapas avanzadas de la enfermedad renal crónica, pero también al desconocimiento de sus beneficios potenciales. Al respecto, los nefrólogos aceptaron que deberían aprender más acerca de estos medicamentos antidiabéticos, porque el tipo de paciente que frecuentemente asiste a su consulta sin duda se beneficiaría, y más teniendo en cuenta que por el gran número de diabéticos los nefrólogos están obligados a manejar directamente al paciente con esta patología.
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Humanos , Fármacos Cardiovasculares , Nefrologistas , Hipoglicemiantes , Cardiotônicos , Colômbia , Diabetes Mellitus Tipo 2 , LiraglutidaRESUMO
La insuficiencia renal es una comorbilidad frecuente en pacientes con diabetes mellitus (DM) e incrementa en ellos el riesgo cardiovascular; la hiperglucemia crónica en pacientes con DM induce una gran cantidad de alteraciones directas e indirectas en la estructura y la función renal, y constituye el principal factor para el desarrollo de la nefropatía diabética y la enfermedad renal terminal. En la presente revisión, se exponen los resultados de los estudios en los que se ha demostrado la alta tolerabilidad de empagliflozina en pacientes diabéticos con insuficiencia renal concomitante en estadios I a III. Empagliflozina, mediante la inhibición de SGLT2, ofrece una terapia novedosa con efectos benéficos no sólo sobre el control glucémico, sino también beneficios cardiovasculares y renales, los cuales han sido demostrados en el estudio EMPA-REG OUTCOME y continúan en evaluación en otros estudios
Chronic kidney disease is a frequent comorbidity in patients with diabetes mellitus (DM) and it increases their cardiovascular risk; chronic hyperglycemia in patients with DM leads to direct and indirect disorders in kidney's structure and function, and it is the principal risk factor for the development of diabetic nephropathy and end-stage renal disease. In the current review, results of studies are exposed in which high tolerability of empagliflozin is exposed in diabetic patients with kidney disease. Empagliflozin by inhibiting SGLT2 provides a novel therapy with benefic effects, not only in glycemic control, but it also has cardiovascular and renal benefits, which they have been demonstrated in the EMPA-REG OUTCOME trial, and continue in evaluation in other studies
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Humanos , Complicações do Diabetes , Complicações do Diabetes/terapia , Diabetes Mellitus , Proteínas de Transporte de Sódio-Glucose , Índice Glicêmico , Nefropatias DiabéticasRESUMO
Cisplatin (Cisp) is an effective antitumor drug; however, it causes severe nephrotoxicity. Minimization of renal toxicity is essential, but the interference of nephroprotective agents, particularly antioxidants, with the antitumor activity of cisplatin is a general concern. We have recently demonstrated that the anti-hypertensive and antioxidant drug carvedilol (CV) protects against the renal damage and increases the survival of tumor-bearing mice without impairing the tumor reduction by cisplatin. So far, reports on the antioxidant mechanism of CV are controversial and there are no data on the impact of CV on the antitumor mechanisms of cisplatin. Therefore, this study addresses the effect of CV on mechanisms underlying the tumor control by cisplatin. CV did not interfere with the biodistribution or the genotoxicity of cisplatin. We also addressed the antioxidant mechanisms of CV and demonstrated that it does not neutralize free radicals, but is an efficient chelator of ferrous ions that are relevant catalyzers in cisplatin nephrotoxicity. The present data suggest that oxidative damage and genotoxicity play different roles in the toxicity of cisplatin on kidneys and tumors and therefore, some antioxidants might be safe as chemoprotectors. Altogether, our studies provide consistent evidence of the beneficial effect of CV on animals treated with cisplatin and might encourage clinical trials.
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Antineoplásicos/toxicidade , Antioxidantes/uso terapêutico , Carbazóis/uso terapêutico , Cisplatino/toxicidade , Rim/efeitos dos fármacos , Propanolaminas/uso terapêutico , Sarcoma 180/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Carbazóis/farmacologia , Carvedilol , Cisplatino/farmacocinética , Cisplatino/farmacologia , Rim/patologia , Masculino , Propanolaminas/farmacologia , Sarcoma 180/patologia , Distribuição TecidualRESUMO
The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors involved in lipid metabolism and glucose utilization, in cell growth, differentiation and apoptosis, and in the regulation of pro-inflammatory genes expression such as cyclooxygenase-2 (COX-2). PPARγ is the main isoform in the renal inner medulla where it is believed to possess nephroprotective actions. In this kidney zone, COX-2 acts as an osmoprotective gene and its expression is modulated by changes in interstitial osmolarity. In the present work we evaluated whether hyperosmolar-induced COX-2 expression is modulated by PPARγ in renal epithelial cells MDCK subjected to high NaCl medium. The results presented herein show that ligand-activated PPARγ repressed COX-2 expression. But more important, the present findings show that hyperosmolar medium decreased PPARγ protein and increases the PPARγ phosphorylated form, which is inactive. ERK1/2 and p38 activation precedes PPARγ disappearance and induced-COX-2 expression. Therefore, the decrease in PPARγ expression is required for hyperosmotic induction of COX-2. We also found that PGE2, the main product of COX-2 in MDCK cells, induced these changes in PPARγ protein. Our results may alert on the long term use of thiazolidinediones (TZD) since they could affect renal medullary function that depends on COX-2 for cellular protection against osmotic stress.