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Background: Activation of the mitogen-activated protein kinase (MAPK) pathway induces uncontrolled cell proliferation in response to inflammatory stimuli. Adriamycin (ADR)-induced nephropathy (ADRN) in rats triggers MAPK activation and pro-inflammatory mechanisms by increasing cytokine secretion, similar to chronic kidney disease (CKD). Activation of the vitamin D receptor (VDR) plays a crucial role in suppressing the expression of inflammatory markers in the kidney and may contribute to reducing cellular proliferation. This study evaluated the effect of pre-treatment with paricalcitol on ADRN in renal inflammation mechanisms. Methods: Male Sprague-Dawley rats were implanted with an osmotic minipump containing activated vitamin D (paricalcitol, Zemplar, 6 ng/day) or vehicle (NaCl 0.9%). Two days after implantation, ADR (Fauldoxo, 3.5 mg/kg) or vehicle (NaCl 0.9%) was injected. The rats were divided into four experimental groups: control, n = 6; paricalcitol, n = 6; ADR, n = 7 and, ADR + paricalcitol, n = 7. Results: VDR activation was demonstrated by increased CYP24A1 in renal tissue. Paricalcitol prevented macrophage infiltration in the glomeruli, cortex, and outer medulla, prevented secretion of tumor necrosis factor-α, and interleukin-1ß, increased arginase I and decreased arginase II tissue expressions, effects associated with attenuation of MAPK pathways, increased zonula occludens-1, and reduced cell proliferation associated with proliferating cell nuclear antigen expression. Paricalcitol treatment decreased the stromal cell-derived factor 1α/chemokine C-X-C receptor type 4/ß-catenin pathway. Conclusions: Paricalcitol plays a renoprotective role by modulating renal inflammation and cell proliferation. These results highlight potential targets for treating CKD.
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Renal endothelial cell (EC) injury and microvascular dysfunction contribute to chronic kidney disease (CKD). In recent years, increasing evidence has suggested that EC undergoes an endothelial-to-mesenchymal transition (EndoMT), which might promote fibrosis. Adriamycin (ADR) induces glomerular endothelial dysfunction, which leads to progressive proteinuria in rodents. The activation of the vitamin D receptor (VDR) plays a crucial role in endothelial function modulation, cell differentiation, and suppression of the expression of fibrotic markers by regulating the production of nitric oxide (NO) by activating the endothelial NO synthase (eNOS) in the kidneys. This study aimed to evaluate the effect of paricalcitol treatment on renal endothelial toxicity in a model of CKD induced by ADR in rats and explore mechanisms involved in EC maintenance by eNOS/NO, angiopoietins (Angs)/endothelium cell-specific receptor tyrosine kinase (Tie-2, also known as TEK) and vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) axis. The results show that paricalcitol attenuated the renal damage ADR-induced with antiproteinuric effects, glomerular and tubular structure, and function protection. Furthermore, activation of the VDR promoted the maintenance of the function and structure of glomerular, cortical, and external medullary endothelial cells by regulating NO production. In addition, it suppressed the expression of the mesenchymal markers in renal tissue through attenuation of (transforming growth factor-beta) TGF-ß1/Smad2/3-dependent and downregulated of Ang-2/Tie-2 axis. It regulated the VEGF/VEGFR2 pathway, which was ADR-deregulated. These effects were associated with lower AT1 expression and VDR recovery to renal tissue after paricalcitol treatment. Our results showed a protective role of paricalcitol in the renal microvasculature that could be used as a target for treating the beginning of CKD.
Assuntos
Doxorrubicina , Insuficiência Renal Crônica , Ratos , Animais , Doxorrubicina/toxicidade , Fator A de Crescimento do Endotélio Vascular , Angiopoietinas , Células Endoteliais , Transdução de Sinais , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
Glycerol injection in rats can lead to rhabdomyolysis, with the release of the intracellular muscle content to the extracellular compartment and acute kidney injury (AKI). Oxidative stress and the inflammatory processes contribute to the disturbances in renal function and structure observed in this model. This study evaluated the effect of calcitriol administration in AKI induced by rhabdomyolysis and its relationship with oxidative damage and inflammatory process. Male Wistar Hannover rats were treated with calcitriol (6 ng/day) or vehicle (0.9% NaCl) for 7 days and were injected with 50% glycerol or saline 3 days after the beginning of calcitriol or saline administration. Four days after glycerol or saline injection, urine, plasma and renal tissue samples were collected for renal function and structural analysis. The oxidative stress and the inflammatory processes were also evaluated. Glycerol-injected rats presented increased sodium fractional excretion and decreased glomerular filtration rates. These alterations were associated with tubular injury in the renal cortex. These animals also presented increased oxidative damage, apoptosis, inflammation, higher urinary excretion of vitamin D-binding protein and decreased cubilin expression in renal tissue. All these alterations were less intense in calcitriol-treated animals. This effect was associated with decreases in oxidative damage and inflammation.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Calcitriol/uso terapêutico , Glicerol/farmacologia , Substâncias Protetoras/uso terapêutico , Rabdomiólise/induzido quimicamente , Rabdomiólise/complicações , Injúria Renal Aguda/sangue , Injúria Renal Aguda/urina , Animais , Apoptose/efeitos dos fármacos , Calcitriol/farmacologia , Cálcio/sangue , Creatina Quinase/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Testes de Função Renal , Masculino , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Proteína de Ligação a Vitamina D/urinaRESUMO
Calcitriol has important effects on cellular differentiation and proliferation, as well as on the regulation of the renin gene. Disturbances in renal development can be observed in rats exposed to angiotensin II (AngII) antagonists during lactation period. The lack of tubular differentiation in losartan-treated rats can affect calcitriol uptake. This study evaluated the effect of calcitriol administration in renal development disturbances in rats provoked by losartan (AngII type 1 receptor antagonist) administration during lactation. Animals exposed to losartan presented higher albuminuria, systolic blood pressure, increased sodium and potassium fractional excretion, and decreased glomerular filtration rate compared to controls. These animals also showed a decreased glomerular area and a higher interstitial relative area from the renal cortex, with increased expression of fibronectin, alpha-SM-actin, vimentin, and p-JNK; and an increased number of macrophages, p-p38, PCNA and decreased cubilin expression. Increased urinary excretion of MCP-1 and TGF-ß was also observed. All these alterations were less intense in the losartan + calcitriol group.The animals treated with calcitriol showed an improvement in cellular differentiation, and in renal function and structure. This effect was associated with reduction of cell proliferation and inflammation.
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Calcitriol/farmacologia , Anormalidades Congênitas/tratamento farmacológico , Anormalidades Congênitas/patologia , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Lactação , Losartan/administração & dosagem , Animais , Biomarcadores , Biópsia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Aleitamento Materno , Quimiocina CCL2/urina , Anormalidades Congênitas/etiologia , Anormalidades Congênitas/fisiopatologia , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Nefropatias/etiologia , Nefropatias/fisiopatologia , Testes de Função Renal , Masculino , Ratos , Fator de Crescimento Transformador beta/urinaRESUMO
INTRODUCTION: Rats exposed to angiotensin II (AII) receptor antagonists during lactation present progressive disturbances in renal development that lead to progressive alterations in renal function and structure. This study evaluates the role of oxidative stress in the renal changes induced by exposure to losartan, a type 1 AII receptor antagonist, in rats during lactation. MATERIALS AND METHODS: Male Wistar pups were divided into: Control, pups of dams that received 2% sucrose solution; Control-tempol, pups of dams that received tempol (0.34 g/l), a superoxide dismutase mimetic compound; Losartan, pups of dams that received losartan (100 mg/kg/day), and Losartan-tempol, pups of dams that received losartan and tempol. Losartan and/or tempol were administered during lactation. Blood and urine samples were collected at 21 or 60 days, and the kidneys were removed. RESULTS: Losartan-treated pups exhibited disturbances in renal function and structure that persisted into adulthood. Tempol treatment reduced oxidative stress and attenuated the changes induced by losartan in the glomerular filtration rate, desmin expression at the glomerular edge, vimentin in tubular cells, as well as apoptosis and inflammatory infiltration in the renal cortex. CONCLUSION: Oxidative stress contributes at least in part to the renal injury observed in pups exposed to losartan during lactation.
Assuntos
Rim/patologia , Lactação/efeitos dos fármacos , Losartan/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Albuminúria/sangue , Albuminúria/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Imuno-Histoquímica , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/fisiopatologia , Testes de Função Renal , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Ratos Wistar , Albumina Sérica/metabolismoRESUMO
BACKGROUND/AIMS: Rats exposed to losartan during lactation exhibit progressive changes in renal function and structure. This study analyzed the early events in pups from dams that received losartan during lactation. METHODS: Male Wistar rats from dams that received 2% sucrose (control, n = 25) or losartan (100 mg/kg/day) diluted in 2% sucrose (n = 33) during lactation were anesthetized 21 days after birth. Blood and urine samples were collected to assess renal function, and kidneys were removed for histological, immunohistochemical, Western blot, lipid peroxidation and glutathione analyses. RESULTS: The group exposed to losartan exhibited increased albuminuria and fractional sodium and potassium excretion, decreased glomerular area and interstitial expansion. Immunohistochemical analyses demonstrated increased tubulointerstitial macrophage infiltration, apoptosis and increased vimentin and α-smooth-muscle-actin expression in animals exposed to losartan. In addition, the glomeruli of animals exposed to losartan exhibited increased peripheral desmin expression and reduced glomerular epithelial protein 1 and podocin expression compared to controls. Lastly, renal lipid peroxidation and glutathione levels were higher in the losartan-treated pups. CONCLUSION: Pups exposed to losartan during lactation exhibited adverse changes in renal function and structure, and tubulointerstitial inflammation at 21 days of age that were associated with apoptosis and oxidative stress.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/toxicidade , Rim/efeitos dos fármacos , Rim/patologia , Lactação , Losartan/administração & dosagem , Losartan/toxicidade , Actinas/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Creatinina/sangue , Desmina/metabolismo , Feminino , Rim/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Vimentina/metabolismoRESUMO
A single injection of adriamycin (ADR) induces marked and persistent proteinuria in rats that progress to glomerular and tubulointerstitial lesions. It has been shown that ADR-induced nephrotoxicity is mediated, at least in part, by oxidative stress that lead to inflammation. Endogenous hydrogen sulfide (H2S) is synthesized from L-cysteine and is an important signaling molecule in inflammation. This study evaluates the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the evolution of renal damage induced by ADR. The rats were injected i.p. with 0.15 M NaCl or PAG (50 mg/kg) 2 h after ADR injection (3.5 mg/kg). Control rats were injected with 0.15 M NaCl or PAG only. Twenty hours urine samples were collected for albuminuria and creatinine measurements on days 1 and 14 after saline or ADR injections and on days 2 and 15 blood samples were collected to measure plasma creatinine, then the rats were killed. The kidneys were removed for H2S formation evaluation, renal lipid peroxidation and glutathione levels, and histological and immunohistochemical analysis. On day 2 after ADR injection the rats presented increase in oxidative stress associated with neutrophils and macrophages influx in renal tissue. On day 15 the rats also presented increased desmin expression at glomerular edge and vimentin in cortical tubulointerstitium, as well as albuminuria. All these alterations were reduced by PAG injection. The protective effect of PAG on ADR nephrotoxicity was associated to decreased H2S formation and to restriction of oxidative stress and inflammation in the renal cortex.
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Alcinos/farmacologia , Doxorrubicina/toxicidade , Glicina/análogos & derivados , Sulfeto de Hidrogênio/metabolismo , Rim/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/toxicidade , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Glicina/farmacologia , Inflamação/induzido quimicamente , Rim/patologia , Córtex Renal/efeitos dos fármacos , Córtex Renal/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Several lines of evidence suggest that angiotensin II (A-II) participates in the postnatal development of the kidney in rats. Many effects of A-II are mediated by mitogen-activated protein kinase (MAPK) pathways. This study investigated the influence that treatment with losartan during lactation has on MAPKs and on A-II receptor types 1 (AT(1)) and 2 (AT(2)) expression in the renal cortices of the offspring of dams exposed to losartan during lactation. In addition, we evaluated the relationship between such expression and changes in renal function and structure. Rat pups from dams receiving 2% sucrose or losartan diluted in 2% sucrose (40 mg/dl) during lactation were killed 30 days after birth, and the kidneys were removed for histological, immunohistochemical, and Western blot analysis. AT(1) and AT(2) receptors and p-p38, c-Jun N-terminal kinases (p-JNK) and extracellular signal-regulated protein kinases (p-ERK) expression were evaluated using Western blot analysis. The study-group rats presented an increase in AT(2) receptor and MAPK expression. In addition, these rats also presented lower glomerular filtration rate (GFR), greater albuminuria, and changes in renal structure. In conclusion, newborn rats from dams exposed to losartan during lactation presented changes in renal structure and function, which were associated with AT(2) receptor and MAPK expression in the kidneys.
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Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Rim/efeitos dos fármacos , Losartan/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores de Angiotensina/análise , Actinas/análise , Animais , Animais Recém-Nascidos , MAP Quinases Reguladas por Sinal Extracelular/análise , Feminino , Proteínas Quinases JNK Ativadas por Mitógeno/análise , Rim/fisiologia , Ratos , Ratos WistarRESUMO
Adult rats submitted to perinatal salt overload presented renin-angiotensin system (RAS) functional disturbances. The RAS contributes to the renal development and renal damage in a 5/6 nephrectomy model. The aim of the present study was to analyze the renal structure and function of offspring from dams that received a high-salt intake during pregnancy and lactation. We also evaluated the influence of the prenatal high-salt intake on the evolution of 5/6 nephrectomy in adult rats. A total of 111 sixty-day-old rat pups from dams that received saline or water during pregnancy and lactation were submitted to 5/6 nephrectomy (nephrectomized) or to a sham operation (sham). The animals were killed 120 days after surgery, and the kidneys were removed for immunohistochemical and histological analysis. Systolic blood pressure (SBP), albuminuria, and glomerular filtration rate (GFR) were evaluated. Increased SBP, albuminuria, and decreased GFR were observed in the rats from dams submitted to high-sodium intake before surgery. However, there was no difference in these parameters between the groups after the 5/6 nephrectomy. The scores for tubulointerstitial lesions and glomerulosclerosis were higher in the rats from the sham saline group compared to the same age control rats, but there was no difference in the histological findings between the groups of nephrectomized rats. In conclusion, our data showed that the high-salt intake during pregnancy and lactation in rats leads to structural changes in the kidney of adult offspring. However, the progression of the renal lesions after 5/6 nephrectomy was similar in both groups.
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Rim/patologia , Rim/fisiopatologia , Lactação , Exposição Materna , Nefrectomia , Sódio na Dieta/administração & dosagem , Animais , Feminino , Imuno-Histoquímica , Gravidez , RatosRESUMO
Cisplatin is an antitumor drug widely used in the treatment of many malignant tumors. However, the most common adverse effect, nephrotoxicity, limits the use of this drug in many cancer patients. Resveratrol is a phytoalexin that presents highly efficient protection in experimental nephrotoxicity models. This study evaluated the effect of resveratrol on cisplatin-induced kidney damage. Male Wistar rats were treated with resveratrol (25 mg/kg b.w., i.p.) before the administration of cisplatin (5 mg/kg b.w., i.p.) and killed 2 or 5 days later. Blood and urine samples were collected and the kidneys were removed. Rats from the cisplatin group showed acute tubular cell necrosis and increased immunostaining for ED1 (macrophages/monocytes) and T-lymphocytes in the renal cortex and outer medulla when compared with the control group. These alterations were less intense in animals pre-treated with resveratrol. Moreover, indicators of renal injury such as increased serum creatinine levels, urinary volume and urinary protein caused by the administration of cisplatin, were also significantly reduced with resveratrol. Increased lipid peroxidation and glutathione depletion in tissue were attenuated by resveratrol. In conclusion, resveratrol attenuated the cisplatin-induced structural and functional renal changes by reducing free radicals and inhibiting inflammatory cell infiltrates.
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Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Cisplatino/toxicidade , Necrose Tubular Aguda/prevenção & controle , Estilbenos/farmacologia , Animais , Creatinina/sangue , Quimioterapia Combinada , Ectodisplasinas/metabolismo , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Proteinúria/induzido quimicamente , Proteinúria/urina , Ratos , Ratos Wistar , Resveratrol , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Micção/efeitos dos fármacosRESUMO
The antioxidant activity of the amino acid glutamine was investigated to obtain protection against peroxidative damage in rat kidney and nephrotoxicity induced by the treatment with a single dose of the antitumoral cisplatin (5mgkg(-1) body weight). The animals were divided into four treatment and control groups of six rats each (n=6). Cisplatin was injected i.p. and glutamine (300mgkg(-1) body weight) was given by gavage 24h before the cisplatin injection. After 24h and 7 days of cisplatin administration, the rats were sacrificed. A single dose of cisplatin resulted in significant reduction in body weight and creatinine clearance, and higher urinary volumes were observed in all groups treated with this antitumor drug (P<0.05). Renal tissue from cisplatin-treated rats showed an increase in malondialdehyde production and increase in glutathione contents 24h and 7 days after cisplatin administration. Pretreatment of rats with glutamine substantially inhibited the increase in the levels of renal glutathione induced by cisplatin 24h after the i.p. injection. The malondialdehyde in the renal tissues was significantly reduced 7 days after cisplatin treatment. However, the reduction in the peroxidative damage did not reach the value of the control group. The protective effects obtained by glutamine pretreatment in peroxidative alterations were not observed in the other parameters studied. These results suggest that glutamine partially protect against cisplatin-induced lipid peroxidation damage, but it was not enough to inhibit cisplatin-induced nephrotoxicity in rats.
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Cisplatino/efeitos adversos , Glutamina/uso terapêutico , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Creatinina/metabolismo , Glutamina/farmacologia , Glutationa/sangue , Nefropatias/induzido quimicamente , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Several studies have suggested that dietary supplementation with antioxidants can influence the response to chemotherapy as well as the development of adverse side effects that result from treatment with antineoplastic agents. The emphasis of the present study was to investigate whether the administration of a single dose of oral glutamine had any protective effect against cisplatin-induced clastogenicity. Cisplatin was administered to Wistar rats either alone or after treatment with glutamine. The rats were treated with glutamine (300 mg/kg b.w.) by gavage 24h before the administration of cisplatin (5mg/kg b.w., i.p.) and then sacrificed 24h after treatment with cisplatin. Glutamine significantly reduced (by about 48%) the clastogenicity of cisplatin in rat bone marrow cells. The antioxidant action of glutamine presumably modulates the clastogenic action of cisplatin.