Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Exp Mol Pathol ; : 104304, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31479659

RESUMO

Diabetes induces time-dependent alterations in urinary bladders. Long-term diabetes causes an underactive bladder. However, the fundamental mechanisms are still elusive. This study aimed to examine the histological changes and the potential molecular pathways affected by long-term diabetes in the rat bladder. Diabetes was induced in 8-week-old male Lewis rats by streptozotocin, while age-matched control rats received citrate buffer only. Forty-four weeks after diabetes induction, bladders were harvested for histological and molecular analyses. The expressions of proteins related to fibrosis, apoptosis and oxidative stress as well as the cellular signaling pathway in the bladder were examined by immunoblotting. Histological examinations illustrated diabetes caused detrusor hypertrophy and fibrotic changes in the bladder. Immunoblotting analysis demonstrated higher collagen I but lower elastin expression in the bladder in diabetic rats. These were accompanied by an increase in the expression of transforming growth factor-beta1, along with the downregulation of matrix metalloptoteinase-1, and upregulation of tissue inhibitor of metalloproteinase-1. Diabetic rats showed an increase in nitrotyrosine, but decrease in nuclear factor erythroid-related factor 2 (Nrf2) levels in the bladder. Enhanced apoptotic signaling was observed, characterized by increased expression of Bcl-2-associated X protein (Bax), decreased expression of Bcl-2, in the diabetic bladder. The nerve growth factor level was decreased in the diabetic bladder. A significant suppression in the protein expressions of phosphorylated extracellular signal-regulated kinases 1/2 was found in diabetic bladders. This study demonstrated that long-term diabetes caused molecular changes that could promote fibrosis and apoptosis in the bladder. Oxidative stress may be involved in this context.

2.
Am J Physiol Renal Physiol ; 317(4): F906-F912, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241994

RESUMO

Bladder dysfunction in diabetes progresses gradually over time. However, the mechanisms of the development are not clear. We tested the hypothesis that oxidative stress plays a key role in the development of diabetic bladder dysfunction using an inducible smooth muscle (SM)-specific superoxide dismutase 2 (Sod2) gene knockout (SM-Sod2 KO) mouse model. Eight-week-old male Sod2lox/lox, SM-CreERT2(ki)Cre/+ mice and wild-type mice were assigned to diabetic or control groups. 4-Hydroxytamoxifen was injected into Sod2lox/lox, SM-CreERT2(ki)Cre/+ mice to activate CreERT2-mediated deletion of Sod2. Diabetes was induced by injection of streptozotocin, whereas control mice were injected with vehicle. Nine weeks later, bladder function was evaluated, and bladders were harvested for immunoblot analysis. Wild-type diabetic mice presented compensated bladder function along with increased nitrotyrosine and MnSOD in detrusor muscle. Induction of diabetes in SM-Sod2 KO mice caused deteriorated bladder function and even greater increases in nitrotyrosine compared with wild-type diabetic mice. Expression levels of apoptosis regulator Bax and cleaved caspase-3 were increased, but apoptosis regulator Bcl-2 expression was decreased in detrusor muscle of both diabetic groups, with more pronounced effects in SM-Sod2 KO diabetic mice. Our findings demonstrate that exaggerated oxidative stress can accelerate the development of bladder dysfunction in diabetic mice and the enhanced activation of apoptotic pathways in the bladder may be involved in the process.

3.
Mol Cell Biochem ; 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30173373

RESUMO

The present study aimed to investigate the inhibitory effects of 10-dehydrogingerdione (10-DHGD) and pentoxifylline (PTX) either individually or in combined form on calcium deposition in high cholesterol diet (HCD)-fed rabbits as compared to atorvastatin (ATOR), and to clarify the underlying mechanisms. Three-months-old male New Zealand white rabbits received either normal chow or HCD for 12 weeks. The latter group was subdivided into five groups and concurrently treated either with vehicle (dyslipidemic control), ATOR, 10-DHGD, PTX or combined 10-DHGD and PTX. Blood samples and aortic tissue were collected for biochemical and histological analyses. HCD-fed rabbits displayed dyslipidemia, inflammation, atherosclerotic lesions, and calcium deposition in aortas as compared to normal group. This was associated with up-regulation of bone morphogenetic protein-2 (BMP-2), wingless-type MMTV integration site family 3A (Wnt3a) mRNA levels and osteopontin expression in their aortic tissue, along with higher serum alkaline phosphatase and osteocalcin levels. Furthermore, a marked decrease in osteoprotegerin, along with a significant increase in receptor activator of NF-κB(RANK) levels, was found in aortic tissue of dyslipidemic rabbits. 10-DHGD and PTX monotherapy significantly modulated the afore-mentioned calcification markers and attenuated aortic calcification to greater extent than ATOR. Combination of 10-DHGD and PTX exerted more anti-calcifying effect than either individual drug. Our findings suggested therapeutic roles of 10-DHGD and PTX against aortic calcium deposition in dyslipidemic rabbits, likely mediated by HDL-raising effect and attenuation of associated inflammation. Combination of 10-DHGD and PTX may represent a promising therapeutic strategy for aortic calcification associated with atherosclerosis.

4.
J Cardiovasc Pharmacol Ther ; 23(6): 551-560, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29742924

RESUMO

Policosanol (POL) is a hypocholesterolemic drug of natural origin and has been shown to reduce circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) in healthy participants. Recently, we have reported that POL can attenuate aortic calcification in diabetic dyslipidemic rats; however, the underlying mechanism is not fully elucidated. We aimed to investigate the effect of POL on aortic calcification and whether PCSK9 has a contributory role and also to examine whether the combination of POL with pentoxifylline (PTX) as anti-tumor necrosis factor α would offer additional benefits. Thirty adult male New Zealand rabbits weighing 1.5 to 2 kg were randomly assigned to 5 groups. One group received standard chow diet and served as normal control group (NC). The other 4 groups received 0.5% wt/wt cholesterol-rich diet for 12 weeks and concurrently treated with placebo, POL, PTX, or a combination of POL and PTX. Sera samples and aortic tissue were collected for biochemical measurements and histological assessment. Rabbits fed a cholesterol-rich diet demonstrated dyslipidemia, increased inflammatory state, and elevated serum levels of PCSK9, compared to the NC group. Aortic calcification was evident in dyslipidemic rabbits, represented by increased calcium deposition and osteopontin expression in aortic tissue, along with elevated serum levels of alkaline phosphatase and osteocalcin. Dyslipidemic rabbits showed a significant upregulation of wingless-type MMTV integration site family 3A and bone morphogenetic protein 2 genes in their aortic tissue. Policosanol significantly reduced circulating PCSK9 levels, suppressed calcification markers, and attenuated aortic calcification. Combination of POL with PTX alleviated aortic calcification to a greater extent than either monotherapy, which may be attributed to further suppression of PCSK9 and calcification markers. These findings suggested that POL exerted anticalcifying effect partly via inhibition of PCSK9. Combination of POL and PTX offered additional benefits and might represent a promising therapeutic option for aortic calcification.

5.
Clin Exp Hypertens ; : 1-7, 2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29667441

RESUMO

Western diet (WD), rich in saturated fat and sugars, has become a risk factor for obesity and metabolic syndrome, however, its effect on endothelial function and vascular remodeling is not fully elucidated. Recent evidence suggests cross-talk between Rho kinase (ROCK) pathway and cardiovascular system. We aimed to investigate the effect of WD on aortic remodeling and the contribution of ROCK signaling. Eight week old male Sprague-Dawley rats were fed either standard chow diet (SD) or high fructose/ high-fat diet, typically as in WD. After 42 weeks, WD-fed rats showed hyperglycemia, dyslipidemia, and hypertension without marked weight gain, compared to SD-fed rats. Significant up-regulation of ROCK-1 and -2, along with a decline in eNOS expression were found in the aortic tissue of WD-fed rats. Additionally, WD-fed rats displayed oxidative stress and fibrosis in their aortic tissues versus controls. Our findings suggest that long-term feeding of WD contributes to endothelial dysfunction and aortic remodeling in adult male rats. ROCK activation seems to be involved in WD-related vascular disorders and may represent a promising therapeutic target.

6.
J Diabetes Complications ; 30(5): 778-85, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27037041

RESUMO

AIMS: Diabetic bladder dysfunction (DBD) has been extensively studied in animal models of type 1 diabetes. We aimed to examine the functional and morphological alterations of the urinary bladder in a type 2 diabetes model, FVB(db/db) mice. METHODS: FVB(db/db) mice and age-matched FVB/NJ control mice were tested at either 12, 24 or 52weeks of age. Body weight, blood glucose and glycated hemoglobin (HbA1c) levels were measured. Bladder function was assessed by measurement of 24-h urination behavior and conscious cystometry. Bladder was harvested for Masson's Trichrome staining and morphometric analysis. RESULTS: The body weights of FVB(db/db) mice were twice as those of FVB/NJ control mice. The blood glucose and HbA1c levels were higher in FVB(db/db) mice at 12 and 24weeks, but not at 52weeks. A significant increase in the mean volume per void, but decrease in the voiding frequency, in FVB(db/db) mice was observed. Cystometry evaluation showed increased bladder capacity, voided volume, and peak micturition pressure in FVB(db/db) mice compared with FVB/NJ mice. Morphometric analysis revealed a significant increase in the areas of detrusor muscle and urothelium in FVB(db/db) mice. In addition, some FVB(db/db) mice, especially males at 12 and 24weeks, showed small-volume voiding during 24-h urination behavior measurement, and detrusor overactivity in the cystometry measurement. CONCLUSIONS: The FVB(db/db) mouse, displaying DBD characterized by not only increased bladder capacity, void volume, and micturition pressure, but also bladder overactivity, is a useful model to further investigate the mechanisms of type 2 diabetes-related bladder dysfunction.


Assuntos
Envelhecimento , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Obesidade/complicações , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária/fisiopatologia , Urotélio/fisiopatologia , Animais , Comportamento Animal , Glicemia , Complicações do Diabetes/sangue , Complicações do Diabetes/patologia , Ingestão de Líquidos , Feminino , Hemoglobina A Glicada/análise , Masculino , Camundongos Endogâmicos , Camundongos Mutantes , Tamanho do Órgão , Caracteres Sexuais , Bexiga Urinária/patologia , Bexiga Urinária Hiperativa/sangue , Bexiga Urinária Hiperativa/patologia , Bexiga Urinária Hiperativa/fisiopatologia , Micção , Urotélio/patologia , Ganho de Peso
7.
Am J Physiol Cell Physiol ; 309(3): C169-78, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25948732

RESUMO

Manganese superoxide dismutase (MnSOD) is considered a critical component of the antioxidant systems that protect against oxidative damage. We are interested in the role of oxidative stress in bladder detrusor smooth muscle (SM) in different disease states. In this study, we generated an inducible, SM-specific Sod2(-/-) mouse model to investigate the effects of MnSOD depletion on the function of the bladder. We crossbred floxed Sod2 (Sod2(lox/lox)) mice with mice containing heterozygous knock-in of a gene encoding a tamoxifen-activated Cre recombinase in the SM22α promoter locus [SM-CreER(T2)(ki)(Cre/+)]. We obtained Sod2(lox/lox),SM-CreER(T2)(ki)(Cre/+) mice and injected 8-wk-old males with 4-hydroxytamoxifen to induce Cre-mediated excision of the floxed Sod2 allele. Twelve weeks later, SM-specific deletion of Sod2 and depletion of MnSOD were confirmed by polymerase chain reaction, immunoblotting, and immunohistochemistry. SM-specific Sod2(-/-) mice exhibited normal growth with no gross abnormalities. A significant increase in nitrotyrosine concentration was found in bladder SM tissue of SM-specific Sod2(-/-) mice compared with both wild-type mice and Sod2(+/+), SM-CreER(T2)(ki)(Cre/+) mice treated with 4-hydroxytamoxifen. Assessment of 24-h micturition in SM-specific Sod2(-/-) mice revealed significantly higher voiding frequency compared with both wild-type and SM-specific Cre controls. Conscious cystometry revealed significantly shorter intercontraction intervals and lower functional bladder capacity in SM-specific Sod2(-/-) mice compared with wild-type mice. This novel model can be used for exploring the mechanistic role of oxidative stress in organs rich in SM in different pathological conditions.


Assuntos
Deleção de Genes , Músculo Liso/enzimologia , Superóxido Dismutase/deficiência , Superóxido Dismutase/genética , Bexiga Urinária/enzimologia , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Estresse Oxidativo/fisiologia
8.
Int J Urol ; 22(4): 410-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25588853

RESUMO

OBJECTIVES: To determine whether diabetes mellitus- and diuresis-induced alterations in the bladder can be reversed in rats. METHODS: Male Sprague-Dawley rats were randomly distributed into eight groups (n = 16 per group): 3 weeks and 11 weeks age-matched controls, 3 weeks and 11 weeks after streptozotocin-induced diabetes mellitus, 3 weeks after diabetes mellitus induction then treated with insulin for 8 weeks, 3 weeks and 11 weeks after 5% sucrose-induced diuresis, and 3 weeks after 5% sucrose-induced diuresis followed by removal of 5% sucrose for 8 weeks. Bodyweight, blood glucose and glycated hemoglobin A1c were monitored. At the designated time-points, 24-h urinary habits were examined, and cystometry was carried out in half of the animals. The bladders from the remaining animals were harvested for histological examination, and quantification of smooth muscle, urothelium and collagen components. RESULTS: Insulin treatment reversed hyperglycemia and polyuria in diabetic animals successfully, which was shown by normalization of blood glucose, glycated hemoglobin A1c and 24-h urinary habits. Subsequently, bodyweight, bladder weight and percentage change of bladder components (smooth muscle, collagen, urothelium) in total bladder cross-sectional area were reversed to almost normal levels, and the bladder dysfunction was mostly reversed by 8 weeks of glycemic control, seen in the cystometry study. Similar alterations and reversed effects were seen in diuretic rats without and with 5% sucrose removal, respectively. CONCLUSIONS: Short-term (3-week induction) diabetes- and polyuria-induced functional and morphological alterations of the bladder can mostly be reversed in rats.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Diurese/fisiologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Animais , Glicemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diurese/efeitos dos fármacos , Hemoglobina A Glicada/metabolismo , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Masculino , Poliúria/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Sacarose/farmacologia , Fatores de Tempo , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos
9.
J Pharm Pharmacol ; 64(6): 862-71, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22571265

RESUMO

OBJECTIVES: Aliskiren is the first in a new class of orally active direct renin inhibitors, approved for the treatment of hypertension. However, the efficacy of aliskiren in diabetic cardiovascular complications remains to be defined. This study aimed to test the hypothesis that aliskiren may enhance the beneficial effects of pioglitazone against cardiovascular injury associated with diabetic nephropathy. METHODS: Diabetic nephropathy was induced in rats by unilateral nephrectomy followed by streptozotocin injection. Diabetic nephropathic rats were orally given vehicle, pioglitazone, aliskiren, or combined pioglitazone and aliskiren for four weeks to compare their effects on cardiovascular injury, particularly myocardial fibrosis. KEY FINDINGS: Pioglitazone treatment significantly attenuated cardiac lipid peroxidation, oxidative injury and myocardial fibrosis in diabetic nephropathic rats. This was associated with up-regulation of transforming growth factor-ß1 and matrix metalloproteinase-2 genes, along with down-regulation of tissue inhibitor of metalloproteinase-2 gene in cardiac tissue. The combination of aliskiren with pioglitazone exerted greater beneficial effect than monotherapy with either drug, on all the aforementioned parameters. CONCLUSIONS: Our findings suggested that aliskiren enhanced the protective effects of pioglitazone against myocardial fibrosis, in experimental diabetic nephropathy. Thus, the combination of aliskiren and pioglitazone may be a potential therapeutic strategy for cardiovascular injury associated with diabetic nephropathy.


Assuntos
Amidas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Fumaratos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Tiazolidinedionas/uso terapêutico , Amidas/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/genética , Modelos Animais de Doenças , Quimioterapia Combinada , Fibrose/prevenção & controle , Fumaratos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Nefrectomia , Estresse Oxidativo/efeitos dos fármacos , Pioglitazona , Ratos , Ratos Wistar , Estreptozocina , Tiazolidinedionas/farmacologia , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
10.
J Cardiovasc Pharmacol Ther ; 17(3): 324-33, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22261714

RESUMO

Pioglitazone has been demonstrated to have beneficial effects on cardiovascular outcomes. However, little is known about its effect on cardiac remodeling associated with diabetic nephropathy. Therefore, this study was designed to study the effects of pioglitazone on cardiac fibrosis and hypertrophy in a rat model of diabetic nephropathy. For this purpose, male Wistar albino rats were randomly assigned into 4 groups (n = 10 per group): normal (N) group, diabetic (D) group, diabetic nephropathic (DN) group received an equal amount of vehicle (0.5% carboxy methyl cellulose), and diabetic nephropathic group treated by oral administration of pioglitazone (10 mg/kg per d) for 4 weeks. Diabetic nephropathy was induced by subtotal nephrectomy plus streptozotocin (STZ) injection. The results revealed that DN rats showed excessive deposition of collagen fibers in their cardiac tissue, along with a marked myocyte hypertrophy. This was associated with a dramatic upregulation of cardiac transforming growth factor-ß1 (TGF-ß1) gene. Furthermore, the gene expression of matrix metalloproteinase 2 (MMP-2) decreased, while the gene expression of tissue inhibitor of metalloproteinase 2 (TIMP-2) increased in the hearts of DN rats. In addition, enhanced lipid peroxidation and myocardial injury, evidenced by a significant increase in their serum creatine kinase-MB level were observed in DN rats. All these abnormalities were ameliorated by pioglitazone administration. Our findings suggest that upregulation of cardiac TGF-ß1 gene along with the imbalance between MMP-2 and TIMP-2 expressions is critically involved in cardiac fibrosis associated with diabetic nephropathy. Pioglitazone can ameliorate cardiac remodeling by suppressing the gene expression of TGF-ß1 and regulating the MMP-2/TIMP-2 system.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/complicações , Fibrose/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Hipoglicemiantes/farmacologia , Tiazolidinedionas/farmacologia , Animais , Glicemia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Fibrose/complicações , Fibrose/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/anatomia & histologia , Cardiopatias/patologia , Hipoglicemiantes/administração & dosagem , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Miocárdio/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Pioglitazona , Distribuição Aleatória , Ratos , Ratos Wistar , Tiazolidinedionas/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA