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1.
Nefrologia (Engl Ed) ; 38(2): 125-135, 2018.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28647049

RESUMO

The term acute tubular necrosis was thought to represent a misnomer derived from morphological studies of human necropsies and necrosis was thought to represent an unregulated passive form of cell death which was not amenable to therapeutic manipulation. Recent advances have improved our understanding of cell death in acute kidney injury. First, apoptosis results in cell loss, but does not trigger an inflammatory response. However, clumsy attempts at interfering with apoptosis (e.g. certain caspase inhibitors) may trigger necrosis and, thus, inflammation-mediated kidney injury. Second, and most revolutionary, the concept of regulated necrosis emerged. Several modalities of regulated necrosis were described, such as necroptosis, ferroptosis, pyroptosis and mitochondria permeability transition regulated necrosis. Similar to apoptosis, regulated necrosis is modulated by specific molecules that behave as therapeutic targets. Contrary to apoptosis, regulated necrosis may be extremely pro-inflammatory and, importantly for kidney transplantation, immunogenic. Furthermore, regulated necrosis may trigger synchronized necrosis, in which all cells within a given tubule die in a synchronized manner. We now review the different modalities of regulated necrosis, the evidence for a role in diverse forms of kidney injury and the new opportunities for therapeutic intervention.


Assuntos
Necrose Tubular Aguda/patologia , Terapia de Alvo Molecular/métodos , Necrose/fisiopatologia , Animais , Apoptose , Oxalato de Cálcio/toxicidade , Cisplatino/toxicidade , Citocinas/fisiologia , Avaliação Pré-Clínica de Medicamentos , Ácido Fólico/toxicidade , Humanos , Rim/irrigação sanguínea , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/tratamento farmacológico , Camundongos , Camundongos Knockout , Proteínas de Transporte da Membrana Mitocondrial/fisiologia , Poro de Transição de Permeabilidade Mitocondrial , Modelos Biológicos , Necrose/classificação , Necrose/tratamento farmacológico , Necrose/imunologia , Traumatismo por Reperfusão/patologia , Terminologia como Assunto
2.
PLoS One ; 12(2): e0168981, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28235038

RESUMO

Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-antitrypsin (AAT), the major serum serine protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy during the early and recovery phase of ischemia-induced acute kidney injury. Mild renal ischemia-reperfusion (I/R) injury was induced in male C57Bl/6 mice by bilateral clamping of the renal artery and vein for 20 min. hAAT (80 mg/kg, Prolastin®) was administered daily intraperitoneally (i.p.) from day -1 until day 7 after surgery. Control animals received the same amount of human serum albumin (hAlb). Plasma, urine and kidneys were collected at 2h, 1, 2, 3, 8 and 15 days after reperfusion for histological and biochemical analysis. hAAT partially preserved renal function and tubular integrity after induction of bilateral kidney I/R injury, which was accompanied with reduced renal influx of macrophages and a significant decrease of neutrophil gelatinase-associated lipocalin (NGAL) protein levels in urine and plasma. During the recovery phase, hAAT significantly decreased kidney injury molecule-1 (KIM-1) protein levels in urine but showed no significant effect on renal fibrosis. Although the observed effect size of hAAT administration was limited and therefore the clinical relevance of our findings should be evaluated carefully, these data support the potential of this natural protein to ameliorate ischemic and inflammatory conditions.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Necrose Tubular Aguda/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , alfa 1-Antitripsina/administração & dosagem , Injúria Renal Aguda/patologia , Animais , Modelos Animais de Doenças , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Necrose Tubular Aguda/fisiopatologia , Camundongos , Traumatismo por Reperfusão/fisiopatologia , alfa 1-Antitripsina/metabolismo
3.
Regul Toxicol Pharmacol ; 84: 35-44, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27993652

RESUMO

This study investigated the pretreatment and post-treatment effects of dipyridamole (20 mg/kg/day, p.o.) in gentamicin-induced acute nephrotoxicity in rats. Rats were administered gentamicin (100 mg/kg/day, i.p.) for 8 days. Gentamicin-administered rats exhibited renal structural and functional changes as assessed in terms of a significant increase in serum creatinine and urea and kidney weight to body weight ratio as compared to normal rats. Renal histopathological studies revealed a marked incidence of acute tubular necrosis in gentamicin-administered rats. These renal structural and functional abnormalities in gentamicin-administered rats were accompanied with elevated serum uric acid level, and renal inflammation as assessed in terms of decrease in interleukin-10 levels. Dipyridamole pretreatment in gentamicin-administered rats afforded a noticeable renoprotection by markedly preventing renal structural and functional abnormalities, renal inflammation and serum uric acid elevation. On the other hand, dipyridamole post-treatment did not significantly prevent uric acid elevation and renal inflammation, and resulted in comparatively less protection on renal function although it markedly reduced the incidence of tubular necrosis. In conclusion, uric acid elevation and renal inflammation could play key roles in gentamicin-nephrotoxicity. Dipyridamole pretreatment markedly prevented gentamicin-induced acute nephrotoxicity, while its post-treatment resulted in comparatively less renal functional protection.


Assuntos
Anti-Inflamatórios/farmacologia , Dipiridamol/farmacologia , Gentamicinas , Necrose Tubular Aguda/tratamento farmacológico , Necrose Tubular Aguda/prevenção & controle , Rim/efeitos dos fármacos , Nefrite/tratamento farmacológico , Nefrite/prevenção & controle , Animais , Biomarcadores/sangue , Creatinina/sangue , Citoproteção , Modelos Animais de Doenças , Interleucina-10/sangue , Rim/metabolismo , Rim/patologia , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/induzido quimicamente , Masculino , Nefrite/sangue , Nefrite/induzido quimicamente , Ratos Sprague-Dawley , Fatores de Tempo , Ácido Úrico/sangue
4.
Toxicol Lett ; 240(1): 105-13, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26546572

RESUMO

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) cell signaling pathway is important in inflammation and cell survival. Inflammation and cell death in the kidney are features of cisplatin-induced AKI. While it is known that cisplatin induces NF-κB signaling in the kidney, the NF-κB responsive genes and the effect of direct NF-κB transcriptional inhibition in cisplatin-induced AKI is not known. Mice injected with cisplatin, 25mg/kg, developed AKI, acute tubular necrosis (ATN) and apoptosis on day 3. Mice were treated with JSH-23 (20 or 40 mg/kg) which directly affects NF-κB transcriptional activity. Kidney function, tubular injury (ATN, serum neutrophil gelatinase-associated lipocalin [NGAL], but not apoptosis) and myeloperoxidase (MPO) activity were significantly improved by JSH-23 (40 mg/kg). Sixty one NF-κB responsive genes were increased by cisplatin of which 21 genes were decreased by JSH-23. Genes that were decreased by JSH-23 that are known to play a role in cisplatin-induced AKI were IL-10, IFN-γ, chemokine [C-C motif] ligand 2 (CCL2) and caspase-1. Another gene, caspase recruitment domain family, member 11 (CARD11), not previously known to play a role in AKI, was increased more than 20-fold and completely inhibited by JSH-23. CXCL1 and TNF-α, known mediators of cisplatin-induced AKI, were decreased by JSH-23. RIPK1 and 3, receptor-interacting serine/threonine-protein kinases, that play an important role in necroptosis, were decreased by JSH-23. In mouse proximal tubule cells in culture, JSH-23 resulted in an increase in apoptosis suggesting that the mechanism of protection against AKI by JSH-23 is not due to a direct effect on proximal tubules. In conclusion, NF-κB transcriptional inhibition in cisplatin-induced AKI ameliorates kidney function and ATN without a significant effect on apoptosis and is associated with a decrease pro-inflammatory mediators and CARD11.


Assuntos
Cisplatino/efeitos adversos , Necrose Tubular Aguda/tratamento farmacológico , NF-kappa B/genética , Fenilenodiaminas/farmacologia , Ativação Transcricional , Proteínas de Fase Aguda , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/genética , Caspase 1/metabolismo , Células Cultivadas , Quimiocina CXCL1/sangue , Cisplatino/administração & dosagem , Creatinina/sangue , Relação Dose-Resposta a Droga , Interleucina-1/sangue , Interleucina-6/sangue , Necrose Tubular Aguda/induzido quimicamente , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Lipocalina-2 , Lipocalinas/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Proteínas Oncogênicas/sangue , Peroxidase/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/sangue
5.
Basic Clin Pharmacol Toxicol ; 116(1): 62-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25052259

RESUMO

To investigate the effect of gamma-aminobutyric acid (GABA) on acute renal injury (ARI), we used here a rat model of acute tubular necrosis induced by the anticancer drug cisplatin (CP). GABA was given orally (100 or 500 mg/kg/day for ten consecutive days), and on the 6th day, some of the treated rats were also injected intraperitoneally with either saline or CP (6 mg/kg). Four days after CP treatment, urine was collected from all rats, which were then anaesthetized for blood pressure and renal blood flow monitoring. This was followed by intravenous injection of norepinephrine for the assessment of renal vasoconstrictor responses. Thereafter, blood and kidneys were collected for measurement of several functional, biochemical and structural parameters. GABA treatment (at 500 but not 100 mg/kg) significantly mitigated all the measured physiological and biochemical indices. Sections from saline- and GABA-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with GABA (500 mg/kg). The concentration of platinum in the cortical tissues was not significantly altered by GABA treatment. The results suggested that GABA can ameliorate CP nephrotoxicity in rats. Pending further pharmacological and toxicological studies, GABA may be considered a potentially useful nephroprotective agent in CP-induced ARI.


Assuntos
Cisplatino/efeitos adversos , Necrose Tubular Aguda/tratamento farmacológico , Ácido gama-Aminobutírico/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Catalase/metabolismo , Cisplatino/administração & dosagem , Creatinina/sangue , Glutationa/metabolismo , Hemodinâmica , Necrose Tubular Aguda/induzido quimicamente , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Masculino , Ratos , Ratos Wistar , Circulação Renal/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Clin Nephrol ; 82(4): 225-30, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25161113

RESUMO

INTRODUCTION: Demographic analysis shows the ageing of the global population and the consequent increase in the age of hospitalized subjects and of patients starting dialysis. Hence, interest in the feasibility, safety, and usefulness of renal biopsy in elderly patients is growing. We examined the data of 131 patients over the age of 75 who underwent renal biopsy. We analyzed the safety of the procedure, treatment, and outcomes. RESULTS: Histological diagnoses included: membranous glomerulonephritis (GN) 20.6%, crescentic GN 12.9%, IgAGN 10.6%, focal segmental glomerulosclerosis 9.1%, acute GN 4.5%, amyloidosis 9.1%, and acute tubular necrosis 3.8%. Mean glomerular obsolescence was 28.9 Â ± 27.9%. Mean age of the patients was 78.7 Â ± 5.73 years. At the time of biopsy, serum creatinine (SCr) was 4.47 Â ± 2.56 mg/dL and proteinuria was 4.82 Â ± 6.78 g/day. Targeted treatment was given to 51.9% of patients, 52.9% of whom had a good clinical response. Eight patients had clinically non-relevant side effects (11.7%). A positive response (defined as a more than 50% reduction of SCr, or by partial or complete remission of proteinuria) was observed in 36 patients (52.9%). 76 patients were monitored for 57 Â ± 9.89 months: 18 patients were on dialysis (follow-up 2.56 Â ± 3.61 months), 15 died (follow-up 58.5 Â ± 13.43 months), and 52 remained under nephrologic observation for 36 Â ± 31 months (SCr was 2.56 Â ± 0.75 mg/dL and proteinuria was 4.82 Â ± 6.78 g/day). CONCLUSION: In our experience, renal biopsy is safe even in very elderly patients; it allowed targeted treatment in 51.9% of patients, 52.9% of whom had a good clinical response, possibly contributing to prolonged patient survival and improved quality of life.


Assuntos
Biópsia/métodos , Nefropatias/patologia , Corticosteroides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Amiloidose/tratamento farmacológico , Amiloidose/patologia , Biópsia/efeitos adversos , Estudos de Coortes , Creatinina/sangue , Feminino , Seguimentos , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/patologia , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/patologia , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/patologia , Hematoma/etiologia , Humanos , Imunossupressores/uso terapêutico , Nefropatias/tratamento farmacológico , Necrose Tubular Aguda/tratamento farmacológico , Necrose Tubular Aguda/patologia , Masculino , Segurança do Paciente , Proteinúria/urina , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento
7.
Int J Urol ; 21(2): 200-3, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23819791

RESUMO

Mannitol has been administered during partial nephrectomy as a renal protective agent for ischemic damage. However, we do not have any high-level clinical evidence of its effectiveness. The aim of the present study was to evaluate the effect of mannitol during open partial nephrectomy by comparing the postoperative renal function of patients who received it and those who did not. We retrospectively reviewed the records of 55 patients who underwent open partial nephrectomy for renal cancer in a solitary kidney from January 1990 to December 2012, and who were followed up postoperatively for at least 6 months. Of the 55 patients, mannitol was given to 20 patients (group M+) and not to the other 35 patients (group M-). We compared not only the postoperative estimated glomerular filtration rate, but also its decrease rate and the incidence of acute kidney injury requiring dialysis in the two groups. There were no significant differences in perioperative patient characteristics between the two groups. Mannitol made no significant difference in both the postoperative estimated glomerular filtration rate and its decrease rate at any point within 6 months of the postoperative period. The incidence of acute kidney injury requiring dialysis was one (5.0%) in group M+ and two (5.7%) in group M-. These findings suggest that there might be no advantage from the administration of mannitol during open partial nephrectomy.


Assuntos
Taxa de Filtração Glomerular/efeitos dos fármacos , Neoplasias Renais/cirurgia , Rim/efeitos dos fármacos , Rim/cirurgia , Manitol/uso terapêutico , Nefrectomia , Diuréticos Osmóticos/uso terapêutico , Feminino , Humanos , Rim/fisiologia , Necrose Tubular Aguda/tratamento farmacológico , Necrose Tubular Aguda/etiologia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Estudos Retrospectivos , Resultado do Tratamento
8.
Braz. j. med. biol. res ; 45(3): 244-249, Mar. 2012. ilus, tab
Artigo em Inglês | LILACS | ID: lil-618052

RESUMO

Animal models of gentamicin nephrotoxicity present acute tubular necrosis associated with inflammation, which can contribute to intensify the renal damage. Hydrogen sulfide (H2S) is a signaling molecule involved in inflammation. We evaluated the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the renal damage induced by gentamicin. Male Wistar rats (N = 8) were injected with 40 mg/kg gentamicin (im) twice a day for 9 days, some of them also received PAG (N = 8, 10 mg·kg-1·day-1, ip). Control rats (N = 6) were treated with saline or PAG only (N = 4). Twenty-four-hour urine samples were collected one day after the end of these treatments, blood samples were collected, the animals were sacrificed, and the kidneys were removed for quantification of H2S formation and histological and immunohistochemical studies. Gentamicin-treated rats presented higher sodium and potassium fractional excretion, increased plasma creatinine [4.06 (3.00; 5.87) mg percent] and urea levels, a greater number of macrophages/monocytes, and a higher score for tubular interstitial lesions [3.50 (3.00; 4.00)] in the renal cortex. These changes were associated with increased H2S formation in the kidneys from gentamicin-treated rats (230.60 ± 38.62 µg·mg protein-1·h-1) compared to control (21.12 ± 1.63) and PAG (11.44 ± 3.08). Treatment with PAG reduced this increase (171.60 ± 18.34), the disturbances in plasma creatinine levels [2.20 (1.92; 4.60) mg percent], macrophage infiltration, and score for tubular interstitial lesions [2.00 (2.00; 3.00)]. However, PAG did not interfere with the increase in fractional sodium excretion provoked by gentamicin. The protective effect of PAG on gentamicin nephrotoxicity was related, at least in part, to decreased H2S formation.


Assuntos
Animais , Masculino , Ratos , Alcinos/farmacologia , Antibacterianos/toxicidade , Gentamicinas/toxicidade , Glicina/análogos & derivados , Sulfeto de Hidrogênio/antagonistas & inibidores , Necrose Tubular Aguda/induzido quimicamente , Creatinina/sangue , Glicina/farmacologia , Sulfeto de Hidrogênio/metabolismo , Imuno-Histoquímica , Necrose Tubular Aguda/tratamento farmacológico , Rim/metabolismo , Ratos Wistar , Fatores de Tempo
9.
Braz J Med Biol Res ; 45(3): 244-9, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22331137

RESUMO

Animal models of gentamicin nephrotoxicity present acute tubular necrosis associated with inflammation, which can contribute to intensify the renal damage. Hydrogen sulfide (H2S) is a signaling molecule involved in inflammation. We evaluated the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the renal damage induced by gentamicin. Male Wistar rats (N = 8) were injected with 40 mg/kg gentamicin (im) twice a day for 9 days, some of them also received PAG (N = 8, 10 mg·kg-1·day-1, ip). Control rats (N = 6) were treated with saline or PAG only (N = 4). Twenty-four-hour urine samples were collected one day after the end of these treatments, blood samples were collected, the animals were sacrificed, and the kidneys were removed for quantification of H2S formation and histological and immunohistochemical studies. Gentamicin-treated rats presented higher sodium and potassium fractional excretion, increased plasma creatinine [4.06 (3.00; 5.87) mg%] and urea levels, a greater number of macrophages/monocytes, and a higher score for tubular interstitial lesions [3.50 (3.00; 4.00)] in the renal cortex. These changes were associated with increased H2S formation in the kidneys from gentamicin-treated rats (230.60 ± 38.62 µg·mg protein-1·h-1) compared to control (21.12 ± 1.63) and PAG (11.44 ± 3.08). Treatment with PAG reduced this increase (171.60 ± 18.34), the disturbances in plasma creatinine levels [2.20 (1.92; 4.60) mg%], macrophage infiltration, and score for tubular interstitial lesions [2.00 (2.00; 3.00)]. However, PAG did not interfere with the increase in fractional sodium excretion provoked by gentamicin. The protective effect of PAG on gentamicin nephrotoxicity was related, at least in part, to decreased H2S formation.


Assuntos
Alcinos/farmacologia , Antibacterianos/toxicidade , Gentamicinas/toxicidade , Glicina/análogos & derivados , Sulfeto de Hidrogênio/antagonistas & inibidores , Necrose Tubular Aguda/induzido quimicamente , Animais , Creatinina/sangue , Glicina/farmacologia , Sulfeto de Hidrogênio/metabolismo , Imuno-Histoquímica , Rim/metabolismo , Necrose Tubular Aguda/tratamento farmacológico , Masculino , Ratos , Ratos Wistar , Fatores de Tempo
10.
Arch Biochem Biophys ; 517(1): 53-70, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22100704

RESUMO

Acute tubular necrosis is a clinical problem that lacks specific therapy and is characterized by high mortality rate. The ischemic renal injury affects the proximal tubule cells causing dysfunction and cell death after severe hypoperfusion. We utilized a cell-based screening approach in a hypoxia-reoxygenation model of tubular injury to search for cytoprotective action using a library of pharmacologically active compounds. Oxygen-glucose deprivation (OGD) induced ATP depletion, suppressed aerobic and anaerobic metabolism, increased the permeability of the monolayer, caused poly(ADP-ribose) polymerase cleavage and caspase-dependent cell death. The only compound that proved cytoprotective either applied prior to the hypoxia induction or during the reoxygenation was adenosine. The protective effect of adenosine required the coordinated actions of adenosine deaminase and adenosine kinase, but did not requisite the purine receptors. Adenosine and inosine better preserved the cellular ATP content during ischemia than equimolar amount of glucose, and accelerated the restoration of the cellular ATP pool following the OGD. Our results suggest that radical changes occur in the cellular metabolism to respond to the energy demand during and following hypoxia, which include the use of nucleosides as an essential energy source. Thus purine nucleoside supplementation holds promise in the treatment of acute renal failure.


Assuntos
Citoproteção/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Rim/citologia , Rim/efeitos dos fármacos , Nucleosídeos de Purina/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glucose/metabolismo , Hipóxia/metabolismo , Hipóxia/patologia , Rim/metabolismo , Rim/patologia , Necrose Tubular Aguda/tratamento farmacológico , Necrose Tubular Aguda/metabolismo , Necrose Tubular Aguda/patologia , Células LLC-PK1 , Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Suínos
11.
J Ren Nutr ; 22(3): 336-43, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22047711

RESUMO

OBJECTIVES: Various protective and therapeutic effects such as antioxidant, anti-inflammatory, anticancer, antihistaminic, and antibacterial effects have been depicted for licorice. However, its biological effects in the kidney are still not clear. Therefore, we aimed to investigate the efficiency of licorice in rats with gentamicin (GM)-induced acute tubular necrosis. DESIGN AND METHODS: Rats were randomized into the control group (only saline for 12 days), licorice group (licorice for 12 days), GM group (GM for 12 days), GM + licorice group, and licorice-treated GM group (licorice for 12 days after taking GM for 12 days). Blood urea, creatinine, and uric acid levels were measured and histopathological analyses of the kidneys were performed. The oxidative side of oxidant-antioxidant balance was evaluated by detecting lipid peroxidation (LPO) and total peroxide levels, and antioxidative side was determined by measuring total antioxidant capacity (TAC) and reduced glutathione (GSH) levels in plasma and kidney tissues. RESULTS: The oxidant-antioxidant balance seemed to be shifted to the oxidative side in the GM group when compared with the control and GM + licorice groups. In GM group, biochemical profiles showed a remarkable increase in blood uric acid, urea, and creatinine levels, and depletion of renal tissue and plasma TAC and GSH levels. In addition, histopathologic studies revealed severe acute tubular necrosis, congestion, and hyaline casts, verifying GM-induced nephrotoxicity. Licorice was effective in reduction of blood urea, creatinine, and uric acid levels, and also effective in decreasing the tubular necrosis score. Licorice treatment also significantly reduced LPO and total peroxide levels, and increased TAC and GSH levels in both renal tissue and blood. Moreover, these changes in rats subjected to the combined therapy (GM + licorice) were significantly less than those of GM group. CONCLUSIONS: Licorice ameliorates GM-induced nephrotoxicity and oxidative damage by scavenging oxygen free radicals, decreasing LPO, and improving antioxidant defense.


Assuntos
Glycyrrhiza/química , Necrose Tubular Aguda/tratamento farmacológico , Necrose Tubular Aguda/patologia , Extratos Vegetais/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Gentamicinas/efeitos adversos , Glutationa/sangue , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos , Ratos , Ratos Wistar
13.
Nefrologia ; 31(4): 464-70, 2011.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-21738249

RESUMO

BACKGROUND: Ischaemia-reperfusion is one of the main causes of kidney complications. The most frequent lesion is acute tubular necrosis. Ozone oxidative preconditioning exerts a modulatory effect of redox state of renal cells in models of ischaemia-reperfusion, by stimulating endogenous antioxidant mechanisms. Similar results have been obtained in more recent studies using ischaemic postconditioning. OBJECTIVES: To evaluate the effect of ozone oxidative postconditioning on renal function and morphology in an ischaemia-reperfusion rat model. METHODS: We used forty female Wistar rats weighing between 150g-200g randomly divided into 4 groups (negative control, positive control, oxygen and ozone). The groups: positive control, oxygen and ozone were subjected to 60 minutes of ischaemia and 10 days of reperfusion. During reperfusion, the oxygen group was given 26mg/kg body weight of oxygen, and the ozone group 0.5mg/kg body weight of ozone, rectally. At the end of the experiment urine and blood samples were taken for renal function tests and kidneys were removed for histological study. RESULTS: The ozone group showed no significant differences for filtration fraction and proteinuria compared to the negative control group. The glomerular filtrate rate, renal plasma flow and creatinine showed a slight improvement in comparison with oxygen and positive control groups. The ozone group showed significantly less overall histological damage than the positive control and oxygen groups. CONCLUSIONS: Ozone postconditioning showed to have a protective effect in preserving renal function and morphology.


Assuntos
Isquemia/tratamento farmacológico , Rim/irrigação sanguínea , Ozônio/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Administração Retal , Animais , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Feminino , Taxa de Filtração Glomerular , Rim/patologia , Rim/fisiopatologia , Necrose Tubular Aguda/tratamento farmacológico , Necrose Tubular Aguda/etiologia , Necrose Tubular Aguda/patologia , Necrose Tubular Aguda/prevenção & controle , Masculino , Oxigênio/administração & dosagem , Oxigênio/uso terapêutico , Ozônio/administração & dosagem , Proteinúria/etiologia , Proteinúria/prevenção & controle , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia
14.
Nephrol Dial Transplant ; 26(3): 814-22, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20817674

RESUMO

BACKGROUND: Cisplatin chemotherapy often causes acute kidney injury in cancer patients. The causative mechanisms of cisplatin-induced acute kidney injury include renal inflammation, activation of p53 tumour suppressor protein and tubular apoptosis. Luteolin, a flavone found in medicinal herbs and plants, has been reported to exhibit anti-inflammatory, antioxidant and anticarcinogenic activities. The purpose of this study was to investigate the anti-apoptotic effect of luteolin on cisplatin-induced acute kidney injury and the molecular mechanism. METHODS: C57BL/6 mice were treated with cisplatin (20 mg/kg) with or without treatment with luteolin (50 mg/kg for 3 days). Renal function, histological changes, degree of oxidative stress and tubular apoptosis were examined. The effects of luteolin on cisplatin-induced expression of renal p53, PUMA-α and Bcl-2 family proteins were evaluated. RESULTS: Treatment of mice with cisplatin resulted in renal damage, showing an increase in blood urea nitrogen and creatinine levels, tubular damage, oxidative stress and apoptosis. Treatment of cisplatin-treated mice with luteolin significantly improved renal dysfunction, reducing tubular cell damage, oxidative stress and apoptosis. Examination of molecules involving apoptosis of the kidney revealed that treatment of cisplatin increased the levels of p53 and its phosphorylation, PUMA-α, Bax and caspase-3 activity that were significantly decreased by treatment with luteolin. CONCLUSION: These results indicate that cisplatin induces acute kidney injury by regulation of p53-dependent renal tubular apoptosis and that luteolin ameliorates the cisplatin-mediated nephrotoxicity through down-regulation of p53-dependent apoptotic pathway in the kidney.


Assuntos
Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Cisplatino/toxicidade , Necrose Tubular Aguda/tratamento farmacológico , Luteolina/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Animais , Western Blotting , Catalase/metabolismo , Glutationa/metabolismo , Testes de Função Renal , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Superóxido Dismutase/metabolismo
15.
Transpl Immunol ; 23(1-2): 45-52, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20412855

RESUMO

Lymphocytes participate in the early pathogenesis of ischemia-reperfusion injury (IRI) in kidney; however, their role during repair is largely unknown. Recent data have shown that Foxp3(+) regulatory T cells (Tregs) traffic into kidney during healing from IRI and directly participate in repair. Since lymphocyte-targeting therapy is currently administered to prevent rejection during recovery from IRI in renal transplants, we hypothesized that mycophenolate mofetil (MMF) would alter Treg trafficking and kidney repair. C57BL/6J and T cell deficient mice underwent unilateral clamping of renal pedicle for 45 min, followed by reperfusion, and were sacrificed at day 10. Mice were treated with saline (C) or MMF (100mg/kg) i.p. daily starting at day 2 until sacrifice (n=5-12/group). MMF worsened kidney tubular damage compared to C at 10 days (cortex and outer medulla: p<0.05) in wild-type mice; tubular apoptotic index was increased in cortex in MMF group as well (p=0.01). MMF reduced the total number of kidney-infiltrating mononuclear cells (p<0.001 versus C) and the percentages of TCRbeta(+)CD4(+) and TCRbeta(+)CD8(+) T cells (p<0.01), but not natural killer (NK), NKT or B lymphocytes. MMF specifically reduced kidney Foxp3(+) Tregs (0.82+/-0.11% versus 1.75+/-0.17%, p<0.05). Tubular proliferative index and tissue levels of basic FGF were increased in MMF group (p<0.05), IL-10 and IL-6 were decreased (p<0.05). To evaluate if MMF effect occurred through non-lymphocytic cells, T cell deficient mice were treated with MMF. Tubular injury in T cell deficient mice was not affected by MMF treatment, though MMF-treated animals had increased VEGF and decreased PDGF-BB protein tissue levels compared to controls (p<0.05). Thus, MMF modifies the structural, epithelial proliferative and inflammatory response during healing, likely through effects on T cells and possibly Tregs. Kidney repair after IRI can be altered by agents that target lymphocytes.


Assuntos
Fatores de Transcrição Forkhead , Imunossupressores/uso terapêutico , Necrose Tubular Aguda/tratamento farmacológico , Rim/patologia , Ácido Micofenólico/análogos & derivados , Traumatismo por Reperfusão/tratamento farmacológico , Linfócitos T Reguladores/citologia , Animais , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Rim/efeitos dos fármacos , Necrose Tubular Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ácido Micofenólico/uso terapêutico , Traumatismo por Reperfusão/terapia
16.
Nephron Exp Nephrol ; 114(2): e69-81, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19907192

RESUMO

BACKGROUND/AIM: Aristolochic acid (AA) nephropathy, first reported as Chinese herbs nephropathy, is a rapidly progressive tubulointerstitial nephropathy that results in severe anemia, interstitial fibrosis and end-stage renal disease. Tubulointerstitial injury was studied in a mouse model of AA nephropathy to determine whether low-dose darbepoetin alpha (DPO) treatment prevents acute tubular necrosis and interstitial fibrosis. METHODS: AA was administered to C3H/He mice intraperitoneally and some mice were also treated with 0.1 microg/kg of DPO weekly starting on the day of AA administration or on day 28. At 28, 56 or 84 days, blood and urine samples were collected and mice were sacrificed for histological assessment of the kidneys. RESULTS: AA-treated mice developed anemia, elevation of serum creatinine, severe tubular injury similar to acute tubular necrosis and progressive interstitial fibrosis. Although early treatment with low-dose DPO had minimal effects on the hematocrit, it significantly ameliorated acute tubular injury and interstitial inflammation through increasing the survival of tubular cells. As a result, it contributed to preservation of peritubular capillaries and reduction of interstitial fibrosis. CONCLUSION: Low-dose DPO treatment conferred protection against acute tubular damage and attenuated interstitial fibrosis in a mouse model of AA nephropathy. Early administration of low-dose DPO may prevent the progression of acute tubular necrosis and the subsequent renal fibrosis in human AA nephropathy.


Assuntos
Eritropoetina/análogos & derivados , Necrose Tubular Aguda/tratamento farmacológico , Túbulos Renais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Ácidos Aristolóquicos , Proliferação de Células/efeitos dos fármacos , Darbepoetina alfa , Modelos Animais de Doenças , Eritropoetina/administração & dosagem , Eritropoetina/uso terapêutico , Fibrose/patologia , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/patologia , Túbulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H
17.
Br J Pharmacol ; 158(6): 1565-78, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19906119

RESUMO

BACKGROUND AND PURPOSE: We have established an in vitro model of acute tubular necrosis in rat kidney tubular cells, using combined oxygen-glucose deprivation (COGD) and screened a library of 1280 pharmacologically active compounds for cytoprotective effects. EXPERIMENTAL APPROACH: We used in vitro cell-based, high throughput, screening, with cells subjected to COGD using hypoxia chambers, followed by re-oxygenation. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and the Alamar Blue assay measured mitochondrial respiration and the lactate dehydrogenase assay was used to indicate cell death. ATP levels were measured using a luminometric assay. KEY RESULTS: Adenosine markedly reduced cellular injury, with maximal cytoprotective effect at 100 microM and an EC(50) value of 14 microM. Inosine was also found to be cytoprotective. The selective A(3) adenosine receptor antagonist MRS 1523 attenuated the protective effects of adenosine and inosine, while an A(3) adenosine receptor agonist provided a partial protective effect. Adenosine deaminase inhibition attenuated the cytoprotective effect of adenosine but not of inosine during COGD. Inhibition of adenosine kinase reduced the protective effects of both adenosine and inosine during COGD. Pretreatment of the cells with adenosine or inosine markedly protected against the fall in cellular ATP content in the cells subjected to COGD. CONCLUSIONS AND IMPLICATIONS: The cytoprotection elicited by adenosine and inosine in a model of renal ischaemia involved both interactions with cell surface adenosine receptors on renal tubular epithelial cells and intracellular metabolism and conversion of adenosine to ATP.


Assuntos
Adenosina/farmacologia , Citoproteção/efeitos dos fármacos , Inosina/farmacologia , Necrose Tubular Aguda/tratamento farmacológico , Adenosina/administração & dosagem , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Hipóxia Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Glucose/metabolismo , Necrose Tubular Aguda/fisiopatologia , Túbulos Renais/citologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , L-Lactato Desidrogenase/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxigênio/metabolismo , Ratos , Receptores Purinérgicos P1/efeitos dos fármacos , Receptores Purinérgicos P1/metabolismo
18.
Ren Fail ; 31(5): 382-92, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19839839

RESUMO

BACKGROUND AND AIMS: Gentamicin (GM) is still considered to be an important antibiotic against life-threatening, gram-negative bacterial infections despite its known nephrotoxic effects. We aimed to evaluate the potential protective effect of atorvastatin (ATO) against GM-induced nephrotoxicity in rats. MATERIALS AND METHODS: The rats were randomly divided into five groups of six animals each: control, GM (100 mg/kg/day), ATO (10 mg/kg/day), GM + ATO, and GM + Vehicle. Kidney function tests, tissue oxidative stress parameters, and histopathological and immunohistochemical studies clarified GM nephrotoxicity. RESULTS: GM caused a marked reduction in renal functions and increased oxidative stress parameters. Histopathological examination revealed tubular necrosis especially in the renal cortex in GM rats. On immunohistochemical evaluation, GM rat showed more intense expressions of mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-kappaB), and inducible nitric oxide synthase (iNOS) compared with control. Kidney function tests and tissue oxidative stress parameters were normalized in the GM + ATO group. Histopathological and immunohistochemical pictures were also greatly ameliorated. CONCLUSIONS: ATO acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects of GM via the inhibition of MAPK and NF-kappaB signaling pathways and iNOS expression.


Assuntos
Ácidos Heptanoicos/farmacologia , Necrose Tubular Aguda/tratamento farmacológico , Necrose Tubular Aguda/patologia , NF-kappa B/efeitos dos fármacos , Pirróis/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Análise de Variância , Animais , Atorvastatina , Distribuição de Qui-Quadrado , Modelos Animais de Doenças , Sequestradores de Radicais Livres/metabolismo , Gentamicinas/farmacologia , Imuno-Histoquímica , Testes de Função Renal , Necrose Tubular Aguda/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Probabilidade , Distribuição Aleatória , Ratos , Ratos Wistar , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Kidney Int ; 74(3): 300-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18480750

RESUMO

The loss of interstitial capillaries is a feature of several experimental models of renal disease and this contributes to secondary kidney injury. Angiopoietin-1 is a secreted growth factor which binds to Tie-2 present on endothelia to enhance cell survival thereby stabilizing capillary architecture in-vitro. Previous studies showed that angiopoietin-1 prevented renal capillary and interstitial lesions following experimental ureteric obstruction. We tested here the effect of angiopoietin-1 treatment on capillary loss and associated tubulointerstitial damage known to follow recovery from folic acid-induced tubular necrosis and acute renal injury. We found that delivery of angiopoietin-1 by adenoviral vectors stabilized peritubular capillaries in folic acid nephropathy but this was accompanied by profibrotic and inflammatory effects. These results suggest that the use of endothelial growth factor therapy for kidney disease may have varying outcomes that depend on the disease model tested.


Assuntos
Angiopoietina-1/efeitos adversos , Fibrose/induzido quimicamente , Inflamação/induzido quimicamente , Necrose Tubular Aguda/tratamento farmacológico , Adenoviridae/genética , Angiopoietina-1/administração & dosagem , Angiopoietina-1/uso terapêutico , Animais , Modelos Animais de Doenças , Ácido Fólico/efeitos adversos , Vetores Genéticos , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Circulação Renal/efeitos dos fármacos
20.
Zhong Xi Yi Jie He Xue Bao ; 6(5): 508-11, 2008 May.
Artigo em Chinês | MEDLINE | ID: mdl-18471417

RESUMO

OBJECTIVE: To investigate the effects of Wenyang Huoxue Recipe (WRHXR), a compound traditional Chinese herbal medicine for warming yang and promoting blood flow, on the expression of angiopoietin mRNA in rats with chronic aristolochic acid nephropathy induced by Caulis Aristolochia Manshuriensis (CAM) decoction, and to explore the protection mechanism of WYHXR against kidney damage. METHODS: Twenty-eight male SD rats were randomly divided into normal control group, CAM group and WYHXR-treated group. Rats in the normal control group (n=8) and CAM group (n=10) were intragastrically administered with normal saline 10 ml/(kg.d) or CAM decoction 10 ml/(kg.d) respectively. Rats in the WYHXR-treated group (n=10) were intragastrically administered with WYHXR 30 g/(kg.d) and CAM decoction 10 ml/(kg.d). The expressions of Ang-l and Ang-2 mRNAs were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) after 20-week treatment. RESULTS: Compared with the normal control group, the expression of Ang-l mRNA was significantly decreased, and the expression of Ang-2 mRNA was significantly increased in the CAM group (P<0.01). Compared with the CAM group, the expression of Ang-l mRNA was increased in the WYHXR-treated group (P<0.01). The expression of Ang-2 mRNA had no significant difference between the CAM group and the WYHXR-treated group (P>0.05). Renal pathology showed that renal damage in WYHXR-treated group was significantly reduced as compared with the CAM group. CONCLUSION: WYHXR can up-regulate the expression of Ang-l mRNA, which may be its action mechanism in protecting the kidneys.


Assuntos
Angiopoietina-1/metabolismo , Ácidos Aristolóquicos/toxicidade , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/tratamento farmacológico , Fitoterapia , Angiopoietina-1/genética , Animais , Aristolochia/química , Medicamentos de Ervas Chinesas/uso terapêutico , Rim/metabolismo , Necrose Tubular Aguda/patologia , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
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