RESUMO
Cisplatin treatment is one of the most commonly used treatments for patients with cancer. However, thirty percent of patients treated with cisplatin develop acute kidney injury (AKI). Several studies have demonstrated the effect of bioactive vitamin D or calcitriol on the inflammatory process and endothelial injury, essential events that contribute to changes in renal function and structure caused by cisplatin (CP). This study explored the effects of calcitriol administration on proximal tubular injury, oxidative stress, inflammation and vascular injury observed in CP-induced AKI. Male Wistar Hannover rats were pretreated with calcitriol (6 ng/day) or vehicle (0.9% NaCl). The treatment started two weeks before i.p. administration of CP or saline and was maintained for another five days after the injections. On the fifth day after the injections, urine, plasma and renal tissue samples were collected to evaluate renal function and structure. The animals of the CP group had increased plasma levels of creatinine and of fractional sodium excretion and decreased glomerular filtration rates. These changes were associated with intense tubular injury, endothelial damage, reductions in antioxidant enzymes and an inflammatory process observed in the renal outer medulla of the animals from this group. These changes were attenuated by treatment with calcitriol, which reduced the inflammation and increased the expression of vascular regeneration markers and antioxidant enzymes.
Assuntos
Injúria Renal Aguda , Cisplatino , Ratos , Animais , Masculino , Cisplatino/farmacologia , Calcitriol/farmacologia , Calcitriol/metabolismo , Ratos Wistar , Antioxidantes/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Estresse Oxidativo , Inflamação/metabolismo , Rim/metabolismoRESUMO
The mechanisms underlying temporomandibular disorders following orofacial pain remain unclear. Hydrogen sulfide (H2S), a newly identified gasotransmitter, has been reported to modulate inflammation. Cystathionine γ-lyase (CSE) is responsible for the systemical production of H2S, which exerts both pro- and antinociceptive effects through inflammation. In the current study, we investigated whether the endogenous H2S production pathway contributes to arousal and maintenance of orofacial inflammatory pain, through the investigation of the effects of a CSE inhibitor, propargyglycine (PAG), in a rat CFA (Complete Freund Adjuvant)-induced temporomandibular inflammation model to mimic persistent pain in the orofacial region. For this, rats received either CFA or saline in the temporomandibular joints (TMJs), and after 3 or 14 days, they received a single injection of PAG or saline and were evaluated for nociception with the von Frey and formalin test. Also, pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) were analyzed in TMJs and trigeminal ganglion (TG). In this last one, glial cells reactivity was also verified. Endogenous H2S production rate were measured in both, TMJ and TG. Our results indicated decreased allodynia and hyperalgesic responses in rats submitted to CFA after injection of PAG. Moreover, PAG inhibited leucocyte migration to temporomandibular synovial fluid after 3 and 14 days of inflammation. PAG was able to reduce levels of CBS, CSE, TNF-α, and IL-1ß in the TMJ and TG, after 13 days of CFA injection. The observed increased activation of glial cells in the trigeminal ganglia on the 14th day of inflammation can be prevented by the highest dose of PAG. Finally, CBS and CSE expression, and endogenous H2S production rate in the TMJ and TG was found higher in rats with persistent temporomandibular inflammation compared to rats injected with saline and PAG was able to prevent this elevation. Our results elucidated the molecular mechanisms by which H2S exerts its pro-inflammatory and pro-nociceptive role in the orofacial region by alterations in both local tissue and TG.
Assuntos
Alcinos/uso terapêutico , Glicina/análogos & derivados , Sulfeto de Hidrogênio/metabolismo , Hiperalgesia/tratamento farmacológico , Inflamação/metabolismo , Dor/tratamento farmacológico , Articulação Temporomandibular/metabolismo , Animais , Cistationina gama-Liase/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Glicina/uso terapêutico , Interleucina-1beta/metabolismo , Masculino , Neuroglia/efeitos dos fármacos , Ratos Wistar , Gânglio Trigeminal/citologia , Gânglio Trigeminal/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND/AIMS: Physical training has beneficial effects on endothelial function and can influence the regeneration of the endothelial cell. We investigated the effect of physical training on cisplatin (CP)-induced acute kidney injury and assessed the impact of training on endothelial structure and function, and on the inflammatory processes in rats. METHODS: We injected male Wistar rats subjected to previous physical training in treadmill running (trained, TR) or not (sedentary, SED) with CP (5 mg/kg) (TR+CP and SED+CP groups, respectively). Five days after the injections, blood and urine samples were collected to evaluate renal function and kidneys were harvested for morphological, immunohistochemical, enzyme-linked immunosorbent assay, and analysis of nitric oxide (NO) levels. RESULTS: Rats treated with CP showed increased levels of plasma creatinine and sodium and potassium fractional excretion. These alterations were associated with increase in tubulointerstitial lesions and macrophage number, reduction of endothelial cells, and increased VEGF, vimentin, and α-smooth muscle actin expression in the outer renal medulla in the SED+CP group. We also found increased levels of renal IL-1ß and increased excretion of monocyte chemoattractant protein-1 and transforming growth factor-ß compared with controls. These changes were milder in trained rats, associated with increased levels of renal tissue NO, and increased expression of p-eNOS and stromal cell-derived factor-1α (a chemokine involved in kidney repair) in the kidneys of CP-injected trained rats. CONCLUSIONS: The protective effect of previous training in CP-treated rats was associated with reduced endothelial cell lesions and increased renal production of NO in trained rats.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Cisplatino/efeitos adversos , Células Endoteliais/patologia , Condicionamento Físico Animal , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Masculino , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos WistarRESUMO
Curcumin is a polyphenol present in the rhizomes of the species Curcuma longa L. ("turmeric," Zingiberaceae), which has been used for centuries as an anti-inflammatory. We aimed to evaluate the anti-inflammatory effects of C. longa in renal injury induced by doxorubicin (DOX, 3.5 mg.kg-1 IV). We studied four groups of Wistar rats: two groups with DOX-induced kidney injury, one fed with standard food and another with standard food mixed with C. longa (5 mg.g-1 ). Two other control groups without kidney injury were fed with the same foods. We measured albuminuria, body weight, and food intake every 2 weeks. After 8 weeks, treatment with C. longa did not change albuminuria, but it significantly attenuated the excretion of urinary inflammatory markers monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-ß (TGF-ß) and significantly attenuated immunostaining for desmin, vimentin, and ED-1+ cells in renal tissues of rats with DOX-induced kidney injury. In addition, treatment with C. longa resulted in significantly lower glomerular and tubule interstitial injury scores, compared with that in the DOX-STD group. In conclusion, administration of powdered rhizomes of C. longa for 8 weeks to rats with DOX-induced kidney injury did not reduce albuminuria but led to a significant decrease in urinary inflammatory markers MCP-1 and TGF-ß and decreased histopathological alterations and immunostaining for desmin, vimentin, and ED-1+ cells kidneys tissues.
Assuntos
Curcuma/química , Doxorrubicina/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Pós/administração & dosagem , Administração Oral , Albuminúria/induzido quimicamente , Albuminúria/tratamento farmacológico , Albuminúria/urina , Animais , Curcumina/administração & dosagem , Curcumina/farmacologia , Dessecação , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , Nefropatias/urina , Masculino , Extratos Vegetais/farmacologia , Pós/farmacologia , Ratos , Ratos Wistar , Rizoma/química , Resultado do Tratamento , Zingiberaceae/químicaRESUMO
Spontaneously hypertensive rats (SHR) display autonomic imbalance and abnormal body temperature (Tb) adjustments. Hydrogen sulfide (H2S) modulates hypoxia-induced hypothermia, but its role in SHR thermoregulation is unknown. We tested the hypothesis that SHR display peculiar thermoregulatory response to hypoxia and that endogenous H2S overproduced in the caudal nucleus of the solitary tract (NTS) of SHR modulates this response. SHR and Wistar rats were microinjected into the fourth ventricle with aminooxyacetate (AOA, H2S-synthezing enzyme inhibitor) or sodium sulfide (Na2S, H2S donor) and exposed to normoxia (21% inspired O2) or hypoxia (10% inspired O2, 30 min). Tb was continuously measured, and H2S production rate was assessed in caudal NTS homogenates. In both groups, AOA, Na2S, or saline (i.e., control; 1 µL) did not affect euthermia. Hypoxia caused similar decreases in Tb in both groups. AOA presented a longer latency to potentiate hypoxic hypothermia in SHR. Caudal NTS H2S production rate was higher in SHR. We suggest that increased bioavailability of H2S in the caudal NTS of SHR enables the adequate modulation of excitability of peripheral chemoreceptor-activated NTS neurons that ultimately induce suppression of brown adipose tissue thermogenesis, thus accounting for the normal hypoxic hypothermia.
Assuntos
Regulação da Temperatura Corporal , Sulfeto de Hidrogênio/metabolismo , Hipotermia Induzida , Hipóxia/fisiopatologia , Ácido Amino-Oxiacético/administração & dosagem , Ácido Amino-Oxiacético/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Hipóxia/complicações , Masculino , Microinjeções , Ratos , Ratos Endogâmicos SHR , Núcleo Solitário/metabolismo , Núcleo Solitário/fisiopatologia , Sulfetos/administração & dosagem , Sulfetos/farmacologiaRESUMO
Hyperglycemia is a major risk factor for kidney diseases. Oxidative stress, caused by reactive oxygen species, is a key factor in the development of kidney abnormalities related to hyperglycemia. The nuclear factor erythroid 2-related factor-2 (Nrf2) plays a crucial role in defending cells against oxidative stress by activating genes that produce antioxidants. L-sulforaphane (SFN), a drug that activates Nrf2, reduces damage caused by hyperglycemia. Hyperglycemic Wistar rats and HEK 293 cells maintained in hyperglycemic medium exhibited decreased Nrf2 nuclear translocation and reduced expression and activity of antioxidant enzymes. SFN treatment increased Nrf2 activity and reversed decreased renal function, oxidative stress and cell death associated with hyperglycemia. To investigate mechanisms involved in hyperglycemia-induced reduced Nrf2 activity, we addressed whether Nrf2 is modified by O-linked ß-N-acetylglucosamine (O-GlcNAc), a post-translational modification that is fueled in hyperglycemic conditions. In vivo, hyperglycemia increased O-GlcNAc-modified Nrf2 expression. Increased O-GlcNAc levels, induced by pharmacological inhibition of OGA, decreased Nrf2 activity in HEK 293 cells. In conclusion, hyperglycemia reduces Nrf2 activity, promoting oxidative stress, cell apoptosis and structural and functional renal damage. Pharmacological treatment with SFN attenuates renal injury. O-GlcNAcylation negatively modulates Nrf2 activity and represents a potential mechanism leading to oxidative stress and renal damage in hyperglycemic conditions.
Assuntos
Hiperglicemia , Nefropatias , Animais , Humanos , Ratos , Antioxidantes/metabolismo , Apoptose , Células HEK293 , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Rim/metabolismo , Nefropatias/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Ratos Wistar , SulfóxidosRESUMO
BACKGROUND/AIMS: The effects of cigarette smoke (CS) on cyclosporine (CsA)-induced nephrotoxicity are poorly studied. This study aims to assess the effects of previous exposure to CS on CsA nephrotoxicity. METHODS: Rats were either exposed to CS or sham (S) procedures for 10 min twice a day for 20 weeks. From the 16th to the 20th week, they received a low-salt diet. Beginning with the 17th week, they were given 2.5 mg/day CsA or vehicle (VH) for 3 weeks. The final groups were VH/CS, CsA/CS, VH/S, and CsA/S. On day 141, glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR), tubulointerstitial fibrosis, and CsA blood levels were measured and immunohistochemistry was analyzed for renal α-smooth muscle actin (SMA), nitrotyrosine, and vimentin. RESULTS: CsA decrease in GFR was enhanced by CS exposure. CsA associated with CS induced higher periglomerular α-SMA and renal nitrotyrosine expression. CsA decreased RBF, but increased RVR, tubulointerstitial fibrosis, and α-SMA and renal vimentin expression. These changes and the CsA blood levels were not affected by CS exposure. CONCLUSION: CS aggravated the CsA-induced impairment of GFR and CS associated with CsA caused the development of periglomerular structural lesions and oxidative stress in a rat model of CsA nephrotoxicity.
Assuntos
Ciclosporina/toxicidade , Imunossupressores/toxicidade , Nefrite Intersticial/induzido quimicamente , Fumar/efeitos adversos , Actinas/metabolismo , Animais , Ciclosporina/sangue , Modelos Animais de Doenças , Sinergismo Farmacológico , Fibrose/induzido quimicamente , Fibrose/metabolismo , Fibrose/patologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Hematócrito , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Imunossupressores/sangue , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Nefrite Intersticial/metabolismo , Nefrite Intersticial/patologia , Ratos , Ratos Wistar , Tirosina/análogos & derivados , Tirosina/metabolismo , Vimentina/metabolismoRESUMO
The role of α-tocopherol during nephrogenesis was investigated in rats subjected to maternal undernutrition, which reduces the number of nephrons. α-tocopherol (350 mg/kg, p.o.) was administered daily to well-nourished or malnourished Wistar dams during pregnancy, or to prenatal undernourished rats during lactation. The kidneys of 1- and 25-day-old offspring were removed to evaluate expression of angiotensin II (Ang II) and to correlate this with expression of proliferating cell nuclear antigen, α-smooth muscle actin, fibronectin and vimentin in the glomeruli and tubulointerstitial space. One-day-old prenatally undernourished rats had reduced expression of Ang II and of kidney development markers, and presented with an enlarged nephrogenic zone. Maternal administration of α-tocopherol restored the features of normal kidney development in undernourished rats. Twenty-five-day-old prenatally undernourished progeny had fewer glomeruli than the control group. Conversely, animals from mothers that received α-tocopherol during lactation presented with the same number of glomeruli and the same glomerular morphometrical profile as the control group. Analyzing the levels of thiobarbituric acid reactive substances in the liver in conjunction with kidney development markers, it is plausible that α-tocopherol had antioxidant and non-antioxidant actions. This study provides evidence that α-tocopherol treatment restored Ang II expression, and subsequently restored renal structural development.
Assuntos
Antioxidantes/farmacologia , Nefropatias/prevenção & controle , Desnutrição/complicações , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , alfa-Tocoferol/farmacologia , Animais , Feminino , Imuno-Histoquímica , Rim/crescimento & desenvolvimento , Rim/metabolismo , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos WistarRESUMO
AIM: Whereas some patients have important changes in body core temperature (Tb) during systemic inflammation, others maintain a normal Tb, which is intrinsically associated to immune paralysis. One classical model to study immune paralysis is the use of repeated administration of lipopolysaccharide (LPS), the so-called endotoxin tolerance. However, the neuroimmune mechanisms of endotoxin tolerance remain poorly understood. Hydrogen sulphide (H2 S) is a gaseous neuromodulator produced in the brain by the enzyme cystathionine ß-synthase (CBS). The present study assessed whether endotoxin tolerance is modulated by hypothalamic H2 S. METHODS: Rats with central cannulas (drug microinjection) and intraperitoneal datalogger (temperature record) received a low-dose of lipopolysaccharide (LPS; 100 µg kg-1 ) daily for four consecutive days. Hypothalamic CBS expression and H2 S production rate were assessed, together with febrigenic signalling. Tolerant rats received an inhibitor of H2 S synthesis (AOA, 100 pmol 1 µL-1 icv) or its vehicle in the last day. RESULTS: Antero-ventral preoptic area of the hypothalamus (AVPO) H2 S production rate and CBS expression were increased in endotoxin-tolerant rats. Additionally, hypothalamic H2 S inhibition reversed endotoxin tolerance reestablishing fever, AVPO and plasma PGE2 levels without altering the absent plasma cytokines surges. CONCLUSION: Endotoxin tolerance is not simply a reflection of peripheral reduced cytokines release but actually results from a complex set of mechanisms acting at multiple levels. Hypothalamic H2 S production modulates most of these mechanisms.
Assuntos
Dinoprostona/biossíntese , Endotoxinas/farmacologia , Sulfeto de Hidrogênio/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Animais , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Citocinas/metabolismo , Dinoprostona/antagonistas & inibidores , Dinoprostona/metabolismo , Modelos Animais de Doenças , Tolerância a Medicamentos , Febre/tratamento farmacológico , Febre/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/metabolismo , Ratos , Ratos WistarRESUMO
Alterations in the renal vasculature during fetal programming can cause disturbances in renal structure and function that persist into adulthood. Calcitriol can affect cellular differentiation and proliferation, and promote endothelial cell maintenance, each of which is a key event in nephrogenesis. Calcitriol is a negative endocrine regulator of the renin gene. Rats exposed to renin-angiotensin system (RAS) antagonists during lactation have been shown to develop renal disorders, which demonstrated that the RAS may play an important role in mammalian kidney development. We evaluated the effects of calcitriol administration on losartan [angiotensin II receptor antagonist (ANGII), AT1]-induced changes in renal differentiation in rats during lactation. Rats treated with losartan showed alterations in renal function and structure that persisted into adulthood. These disruptions included hydronephrosis, papillary atrophy, endothelial dysfunction, and aberrant endothelial structure. These changes were mitigated by treatment with calcitriol. The results of our study showed that animals exposed to AT1 blockade during lactation exhibited altered renal microvasculature differentiation in adulthood that was attenuated by treatment with calcitriol.
RESUMO
BACKGROUND: Interleukin-12 (IL12) participates in the pathophysiology of various experimental types of progressive glomerulonephritis, but its role in acute mesangial glomerulonephritis (AMG) induced by habu snake venom (HSV) has not been determined. This study aims to evaluate the effect of the absence of IL12 on AMG induced by HSV. METHODS: AMG was induced in IL12 knockout (IL12-/-) and C57Bl/6 (IL12+/+) mice by a single i.v. administration of HSV. Vehicle was used in control animals. Mice were studied after 3, 7, and 14 days (D3, D7, and D14). RESULTS: After treatment with HSV, IL12+/+ and -/- mice developed focal glomerular lesions, but groups of both lineages showed no statistical difference concerning albuminuria, serum creatinine, histopathology, number of cells by glomerular tuft, and glomerular tuft area. Compared to IL12+/+ mice, IL12-/- mice showed lower scores of glomerular desmin expression on D7 [1.55 (1.32; 1.65) vs. 1.12 (1.07; 1.22); p < 0.01] and D14 [1.60 (1.55; 1.75) vs. 1.20 (1.15; 1.20); p < 0.001], respectively, and lower scores of glomerular alpha-SMA expression on D14 [0.30 (0.21; 0.38) vs. 0.16 (0.26; 0.36); p < 0.001], respectively. CONCLUSION: The absence of IL12 reduced the activity of mesangial cells, but did not modify the course of HSV-induced AMG in mice.
Assuntos
Glomerulonefrite Membranoproliferativa/metabolismo , Interleucina-12/metabolismo , Animais , Venenos de Crotalídeos , Glomerulonefrite Membranoproliferativa/induzido quimicamente , Interleucina-12/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , TrimeresurusRESUMO
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.
Assuntos
Rim/patologia , Rim/fisiopatologia , Lactação , Exposição Materna , Nefrectomia , Sódio na Dieta/administração & dosagem , Animais , Feminino , Imuno-Histoquímica , Gravidez , RatosRESUMO
Inflammatory events contribute to cisplatin-induced renal damage. Cisplatin promotes increased production of reactive oxygen species, which can activate nuclear factor-kappaB (NF-kappaB) that lead to increased expression of proinflammatory mediators which could intensify the cytotoxic effects of cisplatin. In this study, we evaluated the effect of parthenolide, a selective inhibitor of NF-kappaB, on renal damage caused by cisplatin use. A total of 94 male Wistar rats were divided into six groups: Group A (18 rats) were treated with saline; Group B (12 rats) received dimethylsulfoxide plus saline (the solvent for parthenolide); Group C (12 rats) received parthenolide (3mg/kg) plus saline; Group D (20 rats) received cisplatin (5mg/kg, i.p.); Group E (12 rats) received dimethylsulfoxide plus cisplatin (5mg/kg, i.p.); and Group F (21 rats) received parthenolide (3mg/kg) plus cisplatin (5mg/kg, i.p.). Dimethylsulfoxide or parthenolide were administered at 24h and 1h prior to cisplatin injection, and again at 24h and 48h after. At 2, 3 and 5 days after saline or cisplatin injection, blood and urine samples were collected for measurement of creatinine, sodium and potassium and the kidneys removed for histological, morphometric, electrophoretic mobility shift assay (EMSA), apoptosis and immunohistochemical studies. Cisplatin-treated rats presented higher plasma creatinine, as well as greater immunostaining for ED1 (macrophages/monocytes) and NF-kappaB in the renal cortices and outer medullae. The increase of NF-kappaB activation was confirmed by EMSA. Cisplatin-injected rats also presented higher urinary levels of lipid peroxidation and acute tubular necrosis. All of these alterations were reduced by treatment with parthenolide. This effect seems to be related, at least in part, to the restriction of renal inflammatory process observed in parthenolide+cisplatin treated rats.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/antagonistas & inibidores , Antineoplásicos/toxicidade , Cisplatino/antagonistas & inibidores , Cisplatino/toxicidade , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Sesquiterpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Taxa de Filtração Glomerular , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Nefropatias/patologia , Testes de Função Renal , Medula Renal/patologia , Túbulos Renais/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peróxidos Lipídicos/urina , Masculino , NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxidos/metabolismoRESUMO
Glycerol-induced renal lesions can have many causes, including increased oxidative stress and inflammation. Resveratrol, a polyphenolic phytoalexin found in grapes and red wine, is an antioxidant agent with anti-inflammatory effects. In the present study, we investigated the possible protective effect of resveratrol on glycerol-induced nephrotoxicity. Male Wistar rats were injected intramuscularly with 8 ml/kg of either 50% glycerol (n=18), glycerol+resveratrol (n=22), 0.15 M saline (n=14), saline+carboxymethylcellulose (n=10) or saline+resveratrol (n=8). The rats were killed 3 days after the injections, at which time the kidneys were removed for histological and immunohistochemical studies and lipid peroxidation determination. Blood and urine samples were collected in order to quantify sodium and creatinine. The results of the histological and immunohistochemical studies were scored according to the extent of damage and immunostaining, respectively, in the cortical tubulointerstitium. Lipid peroxidation was estimated by measuring malondialdehyde in renal tissue samples collected from control rats and glycerol-injected rats. By postinjection day 3, glycerol-only treated rats presented increases in plasma creatinine levels, as well as in fractional excretion of sodium and potassium (P<0.001). These increases were less pronounced in glycerol+resveratrol-treated rats (P<0.05). Cortical expression of macrophages, lymphocytes, nuclear factor-kappa B, heme oxygenase-1 and nitrotyrosine was greater in glycerol-treated rats than in controls (P<0.001). In addition, the histological findings for glycerol-treated rats were characteristic of acute tubular necrosis. Resveratrol attenuated all of these alterations (P<0.001). We conclude that resveratrol ameliorates glycerol-induced renal injury by suppressing the inflammatory process and by inhibiting lipid peroxidation.
Assuntos
Antioxidantes/farmacologia , Glicerol/antagonistas & inibidores , Glicerol/toxicidade , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Estilbenos/farmacologia , Animais , Western Blotting , Heme Oxigenase-1/biossíntese , Imuno-Histoquímica , Córtex Renal/efeitos dos fármacos , Córtex Renal/metabolismo , Testes de Função Renal , Peroxidação de Lipídeos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , NF-kappa B/efeitos dos fármacos , Ratos , Ratos Wistar , Resveratrol , Tirosina/análogos & derivados , Tirosina/biossínteseRESUMO
BACKGROUND: Cisplatin-induced renal damage was associated with an inflammatory process. ATP-sensitive potassium channels can be involved in neutrophil migration. This study evaluated the effects of glibenclamide, an ATP-sensitive potassium channel blocker, on cisplatin-induced renal damage. METHODS: A total of 48 Wistar rats received glibenclamide (20 mg/kg/day, s.c.) and 24 h later, these animals, and an additional group of 45 rats, were injected with cisplatin (5 mg/kg, i.p.). In addition, 38 control rats were injected with saline, i.p. Twenty-four hours and 5 days after saline or cisplatin injections blood and urine samples were collected to evaluate renal function and the kidneys were removed for analysis of neutrophil accumulation, tumor necrosis factor-alpha and interleukin-1beta and histological and immunohistochemical studies. RESULTS: Cisplatin injection induced neutrophil recruitment and increased tumor necrosis factor-alpha and interleukin-1beta contents in renal cortices and outer medullae tissues. Cisplatin-treated rats also presented reduction in the glomerular filtration rate, as well as greater immunostaining for ED1 (macrophages/monocytes) and acute tubular necrosis. All of these alterations were reduced by treatment with glibenclamide. These effects seem to be related, at least in part, to the restriction of neutrophil recruitment and inflammatory process observed in the kidneys from glibenclamide+cisplatin-treated rats.
Assuntos
Cisplatino/toxicidade , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Animais , Nefropatias/patologia , Masculino , Ativação de Neutrófilo/efeitos dos fármacos , Ativação de Neutrófilo/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Ratos , Ratos WistarRESUMO
AIMS: Adriamycin (ADR)-induced nephropathy is one of the most experimental models used in progressive kidney disease. A single dose of this drug induces a progressive and irreversible proteinuria that progresses to focal segmental glomerulosclerosis and tubulointerstitial lesions. Regular physical activity has been considered as a therapeutic intervention in several diseases. This study evaluated the influence of previous physical training in renal damage induced by ADR and the role of endothelial lesions and angiogenesis in this process. MAIN METHODS: Male Wistar rats were subjected or not to treadmill running for 4weeks and then injected with ADR (2.5mg/kg, i.v.) or saline. Twenty-four-hour urine samples were collected for albuminuria measurement, and blood samples were collected to measure plasma creatinine 60days after the injections. The kidneys were removed for histological, immunohistochemical, Western blot and ELISA studies. KEY FINDINGS: ADR-treated rats presented increases in plasma creatinine levels, albuminuria, podocyte damage, and enlargement of the tubular interstitial relative area, as well as higher macrophage numbers in the renal cortex, interleukin (IL)-1ß levels in renal tissue and urinary monocyte chemoattractant protein (MCP)-1, which were associated with reduction in vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) expressions and peritubular capillary (PTC) density in renal cortex. These alterations were less intense in the animals subjected to previous exercise training. SIGNIFICANCE: Physical training prior to ADR injection reduced the renal damage induced by this drug. This effect was related to angiogenesis and reduction in the endothelial lesions and inflammatory process in the renal cortex of these animals.
Assuntos
Doxorrubicina , Córtex Renal/irrigação sanguínea , Córtex Renal/patologia , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Corrida , Albuminúria/induzido quimicamente , Albuminúria/patologia , Albuminúria/urina , Animais , Quimiocina CCL2/urina , Creatinina/sangue , Interleucina-1beta/análise , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/patologia , Córtex Renal/efeitos dos fármacos , Nefropatias/patologia , Nefropatias/urina , Masculino , Óxido Nítrico Sintase Tipo III/análise , Podócitos/efeitos dos fármacos , Podócitos/patologia , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
We tested the hypothesis that the neuromodulator hydrogen sulfide (H2S) in the preoptic area (POA) of the hypothalamus modulates the febrigenic signaling differently in sedentary and trained rats. Besides H2S production rate and protein expressions of H2S-related synthases cystathionine ß-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MPST) and cystathionine γ-lyase (CSE) in the POA, we also measured deep body temperature (Tb), circulating plasma levels of cytokines and corticosterone in an animal model of systemic inflammation. Rats run on a treadmill before receiving an intraperitoneal injection of lipopolysaccharide (LPS, 100 µg/kg) or saline. The magnitude of changes of Tb during the LPS-induced fever was found to be similar between sedentary and trained rats. In sedentary rats, H2S production was not affected by LPS. Conversely, in trained rats LPS caused a sharp increase in H2S production rate that was accompanied by an increased CBS expression profile, whereas 3-MPST and CSE expressions were kept relatively constant. Sedentary rats showed a significant LPS-induced release of cytokines (IL-1ß, IL-6, and TNF-α) which was virtually abolished in the trained animals. Correlation between POA H2S and IL-6 as well as TNF-α was observed. Corticosterone levels were augmented after LPS injection in both groups. We found correlations between H2S and corticosterone, and corticosterone and IL-1ß. These data are consistent with the notion that the responses to systemic inflammation are tightly regulated through adjustments in POA H2S production which may play an anti-inflammatory role downmodulating plasma cytokines levels and upregulating corticosterone release.
Assuntos
Regulação da Temperatura Corporal/fisiologia , Febre/fisiopatologia , Sulfeto de Hidrogênio/metabolismo , Condicionamento Físico Animal/fisiologia , Área Pré-Óptica/metabolismo , Animais , Corticosterona/sangue , Corticosterona/metabolismo , Cistationina beta-Sintase/biossíntese , Cistationina beta-Sintase/genética , Cistationina gama-Liase/biossíntese , Cistationina gama-Liase/genética , Citocinas/sangue , Citocinas/metabolismo , Endotoxemia/induzido quimicamente , Endotoxemia/complicações , Endotoxemia/fisiopatologia , Endotoxinas/toxicidade , Indução Enzimática , Febre/etiologia , Inflamação , Masculino , Área Pré-Óptica/fisiopatologia , Ratos , Ratos Wistar , Corrida , Comportamento Sedentário , Sulfurtransferases/biossíntese , Sulfurtransferases/genéticaRESUMO
BACKGROUND: Glycerol injection induces acute tubular necrosis that can progress to interstitial fibrosis. The oxidative stress seen in glycerol-treated animals can activate the nuclear factor kappa B (NF-kappa B) system. The aim of this study was to investigate the expression of NF-kappa B and mitogen-activated protein kinases (MAPKs) in the renal cortex and to determine its relationship with structural and functional renal changes in rats treated with glycerol or glycerol plus pyrrolidine dithiocarbamate (PDTC), a nonspecific NF-kappa B inhibitor with antioxidant properties. METHODS: Male Wistar rats were injected intramuscularly with 8 ml/kg of either 50% glycerol (n=22), glycerol+PDTC (n=25) or 0.15 M saline (n=10). The rats were killed, and the kidneys removed at 5 or 30 days after injection. mmunohistochemical results were scored according to the extent of staining. Interstitial lesions were evaluated through morphometry. Lipid peroxidation was estimated by measuring malondialdehyde in urine samples from control rats and glycerol-injected rats. RESULTS: By postinjection day 5, glycerol-only treated rats presented transitory increases in plasma creatinine levels, as well as in fractional excretion of sodium and potassium (p<0.001), which were attenuated in glycerol+PDTC treated rats (p<0.05). Cortical expression of macrophages and NF-kappa B was greater in glycerol-treated rats than in controls (p<0.001). Glycerol-induced histological nd immunohistochemical changes were attenuated by the addition of PDTC (p<0.001), which also reduced the glycerol-induced increase in urinary malondialdehyde (MDA) levels (p<0.05). CONCLUSIONS: We conclude that PDTC attenuates glycerol-induced renal injury by reducing NF-kappa B expression and decreasing lipid peroxidation in the renal cortex.
Assuntos
Glicerol/toxicidade , Rim/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Animais , Imuno-Histoquímica , Rim/química , Rim/fisiologia , Masculino , Malondialdeído/urina , NF-kappa B/análise , Ratos , Ratos WistarRESUMO
Thermoregulatory responses to lipopolysaccharide (LPS) are affected by modulators that increase (propyretic) or decrease (cryogenic) body temperature (Tb). We tested the hypothesis that central hydrogen sulfide (H2S) acts as a thermoregulatory modulator and that H2S production in the anteroventral preoptic region of the hypothalamus (AVPO) is increased during hypothermia and decreased during fever induced by bacterial lipopolysaccharide (LPS, 2.5mg/kg i.p.) in rats kept at an ambient temperature of 25°C. Deep Tb was recorded before and after pharmacological inhibition of the enzyme cystathionine ß-synthase (CBS - responsible for H2S endogenous production in the brain) combined or not with LPS administration. To further investigate the mechanisms responsible for these thermoregulatory adjustments, we also measured prostaglandin D2 (PGD2) production in the AVPO. LPS caused typical hypothermia followed by fever. Levels of AVPO H2S were significantly increased during hypothermia when compared to both euthermic and febrile rats. Intracerebroventricular (icv) microinjection of aminooxyacetate (AOA, a CBS inhibitor; 100 pmol) neither affected Tb nor basal PGD2 production during euthermia. In LPS-treated rats, AOA caused increased Tb values during hypothermia, along with enhanced PGD2 production. We conclude that the gaseous messenger H2S modulates hypothermia during endotoxic shock, acting as a cryogenic molecule.
Assuntos
Temperatura Corporal/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Choque Séptico/fisiopatologia , Ácido Amino-Oxiacético , Animais , Regulação da Temperatura Corporal/fisiologia , Cistationina beta-Sintase/metabolismo , Febre/induzido quimicamente , Hipotálamo/metabolismo , Hipotermia/fisiopatologia , Hipóxia , Lipopolissacarídeos , Masculino , Microinjeções , Área Pré-Óptica/metabolismo , Ratos , Ratos WistarRESUMO
This study evaluated the effects of aerobic exercise performed both previously and after the induction of diabetes mellitus on changes of renal function and structure in streptozotocin-induced diabetic rats. Female wistar rats were divided into five groups: sedentary control (C + Se); trained control (C + Ex); sedentary diabetic (D + Se); trained diabetic (D + Ex) and previously trained diabetic (D + PEx). The previous exercise consisted of treadmill running for four weeks before the induction of diabetes mellitus. After induction of diabetes mellitus with streptozotocin, the D + PEx, D + Ex and C + Ex groups were submitted to eight weeks of aerobic exercise. At the end of the training protocol, we evaluate the serum glucose, insulin and 17ß-estradiol levels, renal function and structure, proteinuria, and fibronectin, collagen IV and transforming growth factor beta 1 (TGF-ß1) renal expressions. Induction of diabetes mellitus reduced the insulin and did not alter 17ß-estradiol levels, and exercise did not affect any of these parameters. Previous exercise training attenuated the loss of body weight, the blood glucose, the increase of glomerular filtration rate and prevented the proteinuria in the D + PEx group compared to D + Se group. Previous exercise also reduced glomerular hypertrophy, tubular and glomerular injury, as well as the expressions of fibronectin and collagen IV. These expressions were associated with reduced expression of TGF-ß1. In conclusion, our study shows that regular aerobic exercise especially performed previously to induction of diabetes mellitus improved metabolic control and has renoprotective action on the diabetic kidney.