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1.
J Dev Orig Health Dis ; 10(4): 497-501, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30724721

RESUMO

The mechanisms involved in kidney disturbances during development, induced by vitamin D3 deficiency in female rats, that persist into adulthood were evaluated in this study. Female offspring from mothers fed normal (control group, n=8) or vitamin D-deficient (Vit.D-, n=10) diets were used. Three-month-old rats had their systolic blood pressure (SBP) measured and their blood and urine sampled to quantify vitamin D3 (Vit.D3), creatinine, Na+, Ca+2 and angiotensin II (ANGII) levels. The kidneys were then removed for nitric oxide (NO) quantification and immunohistochemical studies. Vit.D- pups showed higher SBP and plasma ANGII levels in adulthood (P<0.05) as well as decreased urine osmolality associated with increases in urinary volume (P<0.05). Decreased expression of JG12 (renal cortex and glomeruli) and synaptopodin (glomeruli) as well as reduced renal NO was also observed (P<0.05). These findings showed that renal disturbances in development in pups from Vit.D- mothers observed in adulthood may be related to the development of angiogenesis, NO and ANGII alterations.


Assuntos
Nefropatias/etiologia , Rim/irrigação sanguínea , Deficiência de Vitamina D/complicações , Animais , Feminino , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Fenômenos Fisiológicos da Nutrição Materna , Ratos
2.
Acta Physiol (Oxf) ; 210(4): 913-27, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24119224

RESUMO

AIM: We hypothesized that hydrogen sulphide (H2 S), acting specifically in the anteroventral preoptic region (AVPO - an important integrating site of thermal and cardiorespiratory responses to hypoxia in which H2 S synthesis has been shown to be increased under hypoxic conditions), modulates the hypoxic ventilatory response. METHODS: To test this hypothesis, we measured pulmonary ventilation (V˙E) and deep body temperature of rats before and after intracerebroventricular (icv) or intra-AVPO microinjection of aminooxyacetate (AOA; CBS inhibitor) or Na2 S (H2 S donor) followed by 60 min of hypoxia exposure (7% O2 ). Furthermore, we assessed the AVPO levels of H2 S of rats exposed to hypoxia. Control rats were kept under normoxia. RESULTS: Microinjection of vehicle, AOA or Na2 S did not change V˙E under normoxic conditions. Hypoxia caused an increase in ventilation, which was potentiated by microinjection of AOA because of a further augmented tidal volume. Conversely, treatment with Na2 S significantly attenuated this response. The in vivo H2 S data indicated that during hypoxia the lower the deep body temperature the smaller the degree of hyperventilation. Under hypoxia, H2 S production was found to be increased in the AVPO, indicating that its production is responsive to hypoxia. The CBS inhibitor attenuated the hypoxia-induced increase in the H2 S synthesis, suggesting an endogenous synthesis of the gas. CONCLUSION: These data provide solid evidence that AVPO H2 S production is stimulated by hypoxia, and this gaseous messenger exerts an inhibitory modulation of the hypoxic ventilatory response. It is probable that the H2 S modulation of hypoxia-induced hyperventilation is at least in part in proportion to metabolism.


Assuntos
Sulfeto de Hidrogênio/farmacologia , Hiperventilação/metabolismo , Hipóxia/complicações , Ácido Amino-Oxiacético/administração & dosagem , Ácido Amino-Oxiacético/farmacologia , Animais , Sulfeto de Hidrogênio/administração & dosagem , Masculino , Área Pré-Óptica , Ratos , Ratos Wistar
3.
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
4.
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
5.
Neuroscience ; 201: 146-56, 2012 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-22120434

RESUMO

Hypoxia causes a regulated decrease in body temperature (Tb), a response that has been aptly called anapyrexia, but the mechanisms involved are not completely understood. The roles played by nitric oxide (NO) and other neurotransmitters have been documented during hypoxia-induced anapyrexia, but no information exists with respect to hydrogen sulfide (H(2)S), a gaseous molecule endogenously produced by cystathionine ß-synthase (CBS). We tested the hypothesis that H(2)S production is enhanced during hypoxia and that the gas acts in the anteroventral preoptic region (AVPO; the most important thermosensitive and thermointegrative region of the CNS) modulating hypoxia-induced anapyrexia. Thus, we assessed CBS and nitric oxide synthase (NOS) activities [by means of H(2)S and nitrite/nitrate (NO(x)) production, respectively] as well as cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) levels in the anteroventral third ventricle region (AV3V; where the AVPO is located) during normoxia and hypoxia. Furthermore, we evaluated the effects of pharmacological modifiers of the H(2)S pathway given i.c.v. or intra-AVPO. I.c.v. or intra-AVPO microinjection of CBS inhibitor caused no change in Tb under normoxia but significantly attenuated hypoxia-induced anapyrexia. During hypoxia there were concurrent increases in H(2)S production, which could be prevented by CBS inhibitor, indicating the endogenous source of the gas. cAMP concentration, but not cGMP and NO(x), correlated with CBS activity. CBS inhibition increased NOS activity, whereas H(2)S donor decreased NO(x) production. In conclusion, hypoxia activates H(2)S endogenous production through the CBS-H(2)S pathway in the AVPO, having a cryogenic effect. Moreover, the present data are consistent with the notion that the two gaseous molecules, H(2)S and NO, play a key role in mediating the drop in Tb caused by hypoxia and that a fine-balanced interplay between NOS-NO and CBS-H(2)S pathways takes place in the AVPO of rats exposed to hypoxia.


Assuntos
Temperatura Corporal/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Hipotermia/etiologia , Hipóxia/complicações , Ácido Amino-Oxiacético/farmacologia , Análise de Variância , Animais , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Hipotermia/tratamento farmacológico , Masculino , Microinjeções , Nitratos/metabolismo , Óxido Nítrico Sintase/metabolismo , Nitritos/metabolismo , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/metabolismo , Ratos , Ratos Wistar , Sulfetos/farmacologia , Terceiro Ventrículo/efeitos dos fármacos , Terceiro Ventrículo/metabolismo , Fatores de Tempo
6.
Braz J Med Biol Res ; 42(1): 38-43, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19219295

RESUMO

Experimental and clinical evidence suggests that angiotensin II (AII) participates in renal development. Renal AII content is several-fold higher in newborn rats and mice than in adult animals. AII receptors are also expressed in higher amounts in the kidneys of newborn rats. The kidneys of fetuses whose mother received a type 1 AII receptor (AT1) antagonist during gestation present several morphological alterations. Mutations in genes that encode components of the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Morphological changes were detected in the kidneys of 3-week-old angiotensin-deficient mice. Mitogen-activated protein kinases (MAPKs) are important mediators that transduce extracellular stimuli to intracellular responses. The MAPK family comprises three major subgroups, namely extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinases (JNK), and p38 MAPK (p38). Important events in renal growth during nephrogenesis such as cellular proliferation and differentiation accompanied by apoptosis on a large scale can be mediated by MAPK pathways. A decrease in glomerulus number was observed in embryos cultured for 48 and 120 h with ERK or p38 inhibitors. Many effects of AII are mediated by MAPK pathways. Treatment with losartan during lactation provoked changes in renal function and structure associated with alterations in AT1 and type 2 AII (AT2) receptors and p-JNK and p-p38 expression in the kidney. Several studies have shown that AII and MAPKs play an important role in renal development. However, the relationship between the effects of AII and MAPK activation on renal development is still unclear.


Assuntos
Rim/embriologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Animais Recém-Nascidos , Rim/efeitos dos fármacos , Rim/enzimologia , Losartan/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Ratos , Cloreto de Sódio na Dieta/efeitos adversos
7.
Braz. j. med. biol. res ; 42(1): 38-43, Jan. 2009. ilus
Artigo em Inglês | LILACS | ID: lil-505416

RESUMO

Experimental and clinical evidence suggests that angiotensin II (AII) participates in renal development. Renal AII content is several-fold higher in newborn rats and mice than in adult animals. AII receptors are also expressed in higher amounts in the kidneys of newborn rats. The kidneys of fetuses whose mother received a type 1 AII receptor (AT1) antagonist during gestation present several morphological alterations. Mutations in genes that encode components of the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Morphological changes were detected in the kidneys of 3-week-old angiotensin-deficient mice. Mitogen-activated protein kinases (MAPKs) are important mediators that transduce extracellular stimuli to intracellular responses. The MAPK family comprises three major subgroups, namely extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinases (JNK), and p38 MAPK (p38). Important events in renal growth during nephrogenesis such as cellular proliferation and differentiation accompanied by apoptosis on a large scale can be mediated by MAPK pathways. A decrease in glomerulus number was observed in embryos cultured for 48 and 120 h with ERK or p38 inhibitors. Many effects of AII are mediated by MAPK pathways. Treatment with losartan during lactation provoked changes in renal function and structure associated with alterations in AT1 and type 2 AII (AT2) receptors and p-JNK and p-p38 expression in the kidney. Several studies have shown that AII and MAPKs play an important role in renal development. However, the relationship between the effects of AII and MAPK activation on renal development is still unclear.


Assuntos
Animais , Camundongos , Ratos , Rim/embriologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Animais Recém-Nascidos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Rim/efeitos dos fármacos , Rim/enzimologia , Losartan/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Cloreto de Sódio na Dieta/efeitos adversos
8.
Pharmacol Res ; 43(1): 77-82, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11207069

RESUMO

Cis -diamminedichloroplatinum(II) (CP), an important antineoplasic drug, shows remarkable toxicity to the kidney. Methods to reduce CP nephrotoxicity include the use of sodium selenite. The aim of the present study was to investigate the interaction between orally administered selenium and CP in the rat. After observing the effects of CP on body growth rate, urinary volume, serum creatinine, serum selenium levels, creatinine clearance, renal malondialdehyde, and glutathione levels, as well as on renal light microscopically visible lesions, the effects of the sodium selenite administration by gavage of 2 mg per kg of body wt. 24 h and 1 h prior to a single CP intraperitoneal injection of 5 mg per kg of body wt. followed by its daily administration for the 7 subsequent days on these parameters, were examined. CP increased renal malondialdehyde, renal glutathione, and serum creatinine and decreased creatinine clearance. Lipid peroxidation is one of the mechanisms by which CP induces renal damage. Selenium treatment decreased the effect of CP on serum creatinine, and renal malondialdehyde levels, but did not affect the other parameters with the exception of kidney necrosis which was also diminished by this treatment.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Rim/efeitos dos fármacos , Rim/patologia , Selênio/administração & dosagem , Administração Oral , Animais , Antineoplásicos/antagonistas & inibidores , Peso Corporal/efeitos dos fármacos , Cisplatino/antagonistas & inibidores , Creatinina/sangue , Glutationa/metabolismo , Intubação Gastrointestinal , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Wistar
9.
Biol Trace Elem Res ; 83(3): 251-62, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11794517

RESUMO

Cisplatin (c-DDP) is a widely used antineoplastic drug whose main side effect is nephrotoxicity. Selenium, administered intravenously or intraperitoneally, has been shown to provided protection against c-DDP-induced nephrotoxicity in rats. In the present study, the protective effect of orally administered sodium selenite on c-DDP toxicity was further examined. Animals treated with c-DDP alone showed increased urinary volume, decreased creatinine clearance (GFR), and a rise in urinary N-acetyl-(beta-D-glucosaminidase) (NAG) isoenzyme B activity. When sodium selenite was given prior to c-DDP, rats showed less GFR decline, delayed urinary volume increases, and no urinary NAG isoenzyme B activity increment. It is suggested that a single oral dose of sodium selenite given prior to c-DDP administration, although not preventing deterioration of renal function, partially protects rats from early proximal tubular injury.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Túbulos Renais Proximais/efeitos dos fármacos , Selenito de Sódio/farmacologia , Acetilglucosaminidase/metabolismo , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Creatinina/metabolismo , Isoenzimas/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Ratos , Ratos Wistar
10.
Teratog Carcinog Mutagen ; 20(6): 341-8, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11074518

RESUMO

Selenium is an essential trace element and a potent anticancer agent. Extensive laboratory studies demonstrate that selenium is an effective chemopreventive agent in various sites in animals. The administration of selenium as a chemopreventive agent raises the question whether the antioxidant selenium, alone or in combination with other dietary antioxidants, could protect non-tumor cells from the clastogenic effect of cisplatin. Therefore, the present study was undertaken to investigate the modulatory effects of selenium, combined or not with vitamin C, on cisplatin-induced chromosomal aberrations in Wistar rat bone marrow cells. The animals were sacrificed 18, 24, or 72 h after cisplatin injection. The results obtained in Wistar rat bone marrow cells showed a slight nonsignificant reduction in the total number of chromosomal aberrations induced by cisplatin (5 mg/kg b.w.) observed in the animals that received a pretreatment with a single dose of selenium (2 mg/kg b.w.). The administration of two doses of selenium (1 mg/kg b.w.) also did not inhibit the chromosomal damage induced by cisplatin. In the present study, no protective response was obtained with either a single or double dose of selenium in rats treated with cisplatin. Furthermore, the combination between selenium+vitamin C was no more effective than vitamin C alone in the protection against damage caused by this antitumor drug. Further investigations, with other forms of selenium, are necessary to elucidate a possible protective role of selenium in clastogenicity induced by free radicals generated by antitumor drugs.


Assuntos
Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Aberrações Cromossômicas , Cisplatino/toxicidade , Selênio/farmacologia , Animais , Ácido Ascórbico/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/ultraestrutura , Masculino , Ratos , Ratos Wistar
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