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1.
Diabetologia ; 54(10): 2724-35, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21755314

RESUMO

AIM/HYPOTHESIS: We examined whether the renin inhibitor, aliskiren, provides similar or greater protection than ACE inhibition from non-proliferative diabetic retinopathy and from the proliferative neoangiogenesis of oxygen-induced retinopathy. METHODS: Transgenic (mRen-2)27 rats, which overexpress mouse renin and angiotensin in extra-renal tissues, were studied. For diabetic studies, non-diabetic, diabetic (streptozotocin, 55 mg/kg), diabetic + aliskiren (10 mg kg(-1) day(-1), pump), or diabetic + lisinopril (10 mg kg(-1) day(-1), drinking water) rats were evaluated over 16 weeks. For oxygen-induced retinopathy studies, rats were exposed to 80% oxygen (22 h/day) from postnatal days 0 to 11, and then room air from postnatal days 12 to 18. Aliskiren (10 or 30 mg kg(-1) day(-1), pump) or lisinopril (10 mg kg(-1) day(-1), drinking water) was administered during retinopathy development between postnatal days 12 and 18. RESULTS: Systolic BP in diabetic (mRen-2)27 rats was reduced with 10 mg kg(-1) day(-1) aliskiren, but only lisinopril normalised systolic blood pressure. In diabetic (mRen-2)27 rats, 10 mg kg(-1) day(-1) aliskiren and lisinopril reduced retinal acellular capillaries and leucostasis to non-diabetic levels. In oxygen-induced retinopathy, neoangiogenesis and retinal inflammation (leucostasis, ED-1 immunolabelling) were partially reduced by 10 mg kg(-1) day(-1) aliskiren and normalised by 30 mg kg(-1) day(-1) aliskiren, whereas lisinopril normalised neoangiogenesis and reduced leucostasis and ED-1 immunolabelling. Aliskiren and lisinopril normalised retinal vascular endothelial growth factor expression; however, only aliskiren reduced intercellular adhesion molecule-1 to control levels. CONCLUSIONS/INTERPRETATION: Aliskiren provided similar or greater retinal protection than ACE inhibition and may be a potential treatment for diabetic retinopathy.


Assuntos
Amidas/uso terapêutico , Retinopatia Diabética/induzido quimicamente , Retinopatia Diabética/tratamento farmacológico , Fumaratos/uso terapêutico , Oxigênio/toxicidade , Renina/metabolismo , Animais , Animais Geneticamente Modificados , Retinopatia Diabética/metabolismo , Feminino , Lisinopril/uso terapêutico , Camundongos , Neovascularização Patológica/tratamento farmacológico , Ratos , Renina/antagonistas & inibidores , Renina/genética
2.
J Comp Neurol ; 519(3): 506-27, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21192081

RESUMO

Retinal neovascularization, such as that occurring in proliferative diabetic retinopathy and retinopathy of prematurity, can have serious effects on visual function. By using a mouse model of neovascularization, oxygen-induced retinopathy (OIR), the interplay among angiogenesis, neuronal function, and the macro- and micro-glial response was explored. OIR was induced by exposure of mice to 75% oxygen from postnatal day 7 (P7) to P11 and then room air until P18. Controls were reared in room air. Blood vessel development was assessed by using fluorescence histochemistry. Aberrant intravitreal neovascularization was present across all eccentricities of retina in mice with OIR, whereas the number of vessels present in the deep plexus was reduced in the central regions. Neuronal function of both the rod and cone pathways, assessed by using the electroretinogram, was found to be significantly reduced in OIR. This may in part be explained by an alteration in photoreceptor outer segment morphology and also a loss of neurons and their synapses in the inner nuclear and plexiform layers of the central retina. In addition, there was an increase in the number of gliotic Müller cells and microglia in mice with OIR and the increase in the number of these cells correlated with the absence of the deep plexus. This indicates that the activity of both macro- and microglia is altered in regions where the deep plexus blood supply is deficient. Treatments or genetic manipulations directed toward amelioration of proliferative retinopathy need to address not only the vascular changes but also the alterations in neuronal and macro- and microglial function.


Assuntos
Modelos Animais de Doenças , Neuroglia/metabolismo , Retina/fisiologia , Neovascularização Retiniana/fisiopatologia , Retinopatia da Prematuridade/fisiopatologia , Animais , Animais Recém-Nascidos , Eletrorretinografia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/citologia , Neuroglia/patologia , Células Fotorreceptoras de Vertebrados/citologia , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/citologia , Neovascularização Retiniana/patologia , Vasos Retinianos/fisiologia , Vasos Retinianos/fisiopatologia , Retinopatia da Prematuridade/patologia
3.
Neuroscience ; 161(1): 195-213, 2009 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-19298848

RESUMO

The bio-active peptide, angiotensin II (Ang II), has been suggested to exert a neuromodulatory effect on inner retinal neurons. In this study, we examined the distribution of angiotensin receptors (ATRs) in the developing and mature rat retina and optic nerve using immunofluorescence immunocytochemistry. Double-labeling experiments were performed with established markers to identify different retinal cell populations. In adult retinae, ATRs were observed on neurons involved in "ON" pathways of neurotransmission. Angiotensin II type 1 receptors (AT(1)Rs) were expressed by a sub-population of "ON" cone bipolar cells that also labeled for G alpha(0) and islet-1. Extra-neuronal expression of AT(1)Rs was evident on retinal astrocytes, Müller cells and blood vessels. Immunoreactivity for the angiotensin II type 2 receptor (AT(2)R) was observed on conventional and displaced GABAergic amacrine cells. Co-localization studies showed that AT(2)R-expressing amacrine cells constituted at least two separate sub-populations. Cell counts revealed that all wide-field amacrine cells expressing protein kinase C-alpha were also AT(2)R-positive; a further subset of amacrine cells expressing AT(2)Rs and stratifying in sublamina "b" of the inner plexiform layer (IPL) was identified. Developmental expression of AT(1)Rs was dynamic, involving multiple inner neuronal classes. At postnatal day 8 (P8), AT(1)R immunoreactivity was observed on putative ganglion cells. The characteristic bipolar cell labeling observed in adults was not evident until P13. In contrast, AT(2)Rs were detected as early as P2 and localized specifically to amacrine cells from this age onward. These data provide further evidence for the potential role of angiotensin II in the modulation of retinal neurons and glia. The differential pattern of expression of these receptors across these cell types is similar to that observed in the brain and suggests that a similar functional role for Ang II may also exist within the retina.


Assuntos
Neuroglia/metabolismo , Neurônios/metabolismo , Receptor Tipo 1 de Angiotensina/biossíntese , Receptor Tipo 2 de Angiotensina/biossíntese , Retina/metabolismo , Células Amácrinas/metabolismo , Animais , Animais Recém-Nascidos , Regulação da Expressão Gênica no Desenvolvimento , Imuno-Histoquímica , Ratos , Ratos Sprague-Dawley , Retina/citologia , Retina/crescimento & desenvolvimento , Vasos Retinianos/metabolismo , Ácido gama-Aminobutírico/metabolismo
4.
Artigo em Inglês | MEDLINE | ID: mdl-18083506

RESUMO

To establish the effect of dietary omega-3 PUFA on angiotensin II (ANG II)-mediated hypertension, male TGR (mRen-2)27 (Ren-2) rats (animals with high ANG II activity) were maintained on a diet either deficient or sufficient in omega-3 PUFA from conception. Half the animals on each diet were treated with the angiotensin-converting enzyme inhibitor, perindopril, from birth. Ren-2 rats fed the omega-3 PUFA deficient diet were significantly more hypertensive than those fed the omega-3 PUFA sufficient diet. Perindopril reduced the blood pressure of both omega-3 PUFA-deficient and omega-3 PUFA-sufficient diet-fed Ren-2 rats. Body weight, body fat and plasma leptin were reduced by perindopril treatment but not affected by omega-3 PUFA supply. Given that the elevated blood pressure of the Ren-2 rat is mediated by ANG II, the data suggest that omega-3 PUFA may reduce hypertension via the renin-angiotensin system.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Ácidos Graxos Ômega-3/administração & dosagem , Hipertensão/terapia , Perindopril/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Angiotensina II/sangue , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Hipertensão/sangue , Hipertensão/dietoterapia , Hipertensão/tratamento farmacológico , Masculino , Ratos , Renina/sangue
5.
J Endocrinol ; 180(2): 311-24, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14765984

RESUMO

There is accumulating evidence that local renin-angiotensin systems (RASs) influence cell growth and organ function in a variety of tissues including the ovary. The first aim of this study was to characterise the cellular location of RAS components in the rat ovary. This was facilitated by the use of the hypertensive transgenic (mRen-2)27 rat which overexpresses renin and angiotensin in extra-renal tissues. Comparisons were made with normal Sprague-Dawley (SD) rats. The second aim was to determine if the upregulated RAS of the transgenic (mRen-2)27 rat and infusion of angiotensin II (ANG II) in SD rats influences follicle number and litter size. Gene expression, immunohistochemical and autoradiographic techniques were used to identify a discrete RAS including ANG II receptors in the ovarian stroma, follicles (particularly atretic) and to a lesser extent corpora lutea. The RAS at these sites was most abundant in homozygous (HMZ) followed by heterozygous (HTZ) (mRen-2)27 rats and then SD rats. Large antral and preovulatory follicles and litter size were reduced in (mRen-2)27 rats. In HMZ (mRen-2)27 rats and SD rats infused with ANG II, angiotensin 1a (AT(1a)) receptor mRNA in the ovarian stroma was lower than control SD rats and was associated with a reduction in large antral and preovulatory follicles. These findings indicate that upregulation of the ovarian RAS in the rat influences follicular development and, potentially, reproductive capacity.


Assuntos
Angiotensina II/farmacologia , Hipertensão/metabolismo , Folículo Ovariano/metabolismo , Renina/genética , Angiotensina II/metabolismo , Animais , Animais Geneticamente Modificados , Feminino , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Tamanho da Ninhada de Vivíparos , Folículo Ovariano/efeitos dos fármacos , Peptidil Dipeptidase A/análise , Gravidez , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/análise , Renina/metabolismo
6.
Diabet Med ; 20(8): 607-21, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12873287

RESUMO

The relationship between the renin-angiotensin system (RAS) and the progression of diabetic renal disease has been a major focus of investigation over the past 20 years. More recently, experimental and clinical studies have also suggested that the RAS may have a pathogenetic role at other sites of micro- and macrovascular injury in diabetes. Complementing major advances into the understanding of the local, as distinct from the systemic RAS, a number of large clinical trials have examined whether blockade of the RAS might provide protection from the long-term complications of diabetes, beyond that due to blood pressure reduction alone. While some controversy remains, these studies have, in general, suggested that angiotensin converting enzyme (ACE) inhibition and more recently, angiotensin receptor blockade reduce the development and progression of diabetic nephropathy, cardiovascular disease and possibly retinopathy. This review will focus on recent developments in our understanding of the tissue-based RAS and its role in end-organ injury in diabetes, the results of recent clinical trials and newer strategies for the pharmacological manipulation of the RAS.


Assuntos
Angiopatias Diabéticas/etiologia , Nefropatias Diabéticas/etiologia , Retinopatia Diabética/etiologia , Angiotensina II/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina , Angiopatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Substâncias de Crescimento/fisiologia , Humanos , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia
7.
J Vasc Res ; 38(6): 527-35, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11740151

RESUMO

Despite the use of laser photocoagulation and knowledge of the beneficial effects of good glycaemic control, visual loss due to diabetic retinopathy remains the commonest cause of blindness in the working population. This visual loss is principally the result of proliferative diabetic retinopathy and macular oedema. The processes by which diabetes mellitus results in retinopathy are incompletely understood, but recent evidence has suggested a pathogenetic role for the renin-angiotensin system (RAS) and vascular endothelial growth factor (VEGF) in the eye in response to chronic hyperglycaemia. This review will explore evidence of a local RAS in the eye, the involvement of VEGF in diabetic retinopathy and the interaction between the RAS and VEGF in the pathogenesis of retinal neovascularization.


Assuntos
Retinopatia Diabética/etiologia , Fatores de Crescimento Endotelial/fisiologia , Linfocinas/fisiologia , Neovascularização Patológica/etiologia , Sistema Renina-Angiotensina/fisiologia , Vasos Retinianos , Animais , Humanos , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
9.
Diabetologia ; 44(7): 878-82, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11508273

RESUMO

AIMS/HYPOTHESIS: Changes in podocyte number and morphology have been implicated in the pathogenesis of proteinuria and the progression of human and experimental kidney disease. This study sought to examine podocyte foot process and slit pore architecture in experimental diabetic nephropathy and to determine whether such changes were modified with renoprotective intervention by blockade of the renin-angiotensin system. METHODS: The number of filtration slits per 100 microm of glomerular basement membrane was assessed by transmission electron microscopy and quantitated histomorphometrically in control animals and in rats with 24 weeks of streptozotocin-induced diabetes. Diabetic rats were either untreated or received the angiotensin converting enzyme inhibitor ramipril, or the angiotensin II type 1 receptor antagonist, valsartan. RESULTS: When compared with control animals, diabetes was associated with a decrease in the number of slit pores per unit length of glomerular basement membrane, indicative of podocyte foot process broadening. Both ramipril and valsartan attenuated these ultrastructural changes to a similar degree. These differences remained after correcting for glomerular volume as a possible confounding variable. CONCLUSION/INTERPRETATION: Preservation of podocyte architecture could contribute to the renoprotective effects of renin-angiotensin system blockade in diabetic nephropathy.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Experimental/fisiopatologia , Ramipril/uso terapêutico , Sistema Renina-Angiotensina/fisiologia , Tetrazóis/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico , Animais , Membrana Basal/efeitos dos fármacos , Membrana Basal/ultraestrutura , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Modelos Animais de Doenças , Progressão da Doença , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/efeitos dos fármacos , Valsartana
10.
Nephrol Dial Transplant ; 16(7): 1343-9, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11427623

RESUMO

BACKGROUND: We have previously reported that severe glomerulosclerosis progressively develops in the streptozotocin (STZ) diabetic transgenic (mRen-2)27 rat. In this diabetic model, monotherapy with either angiotensin converting enzyme inhibition (ACEI) or angiotensin type 1 (AT(1)) receptor blockade is largely renoprotective. The objective of the present study was to determine if a combination therapy at lower doses than monotherapy would confer greater renoprotection. METHODS: At 6 weeks of age, non-diabetic control and STZ diabetic female heterozygous Ren-2 rats were randomized to receive vehicle, the AT(1) receptor blocker valsartan (V, 20 mg/kg/day), the ACEI perindopril (P, 6 mg/kg/day), or a combination of low-dose V+P (V, 3 mg/kg/day plus P, 0.5 mg/kg/day) for 12 weeks. RESULTS: Systolic blood pressure was lowered with all treatments, but the greatest reductions were observed with V monotherapy and combination V+P therapy. All treatments reduced albuminuria, the decline in glomerular filtration rate, and cortical collagen staining, to the same extent. The glomerulosclerotic index was increased with diabetes and reduced with V and P monotherapy. However, the low-dose combination therapy was more effective than single therapy and reduced severe glomerulosclerosis to levels observed in non-diabetic controls. CONCLUSIONS: Monotherapy with either V or P reduced blood pressure and retarded the decline in renal function and glomerulosclerosis in the diabetic Ren-2 rat. Combination therapy has the additional benefit of requiring only low doses of AT(1) receptor blockade and ACEI to achieve superior renoprotective effects in this diabetic nephropathy model.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Perindopril/uso terapêutico , Renina/genética , Tetrazóis/uso terapêutico , Valina/uso terapêutico , Animais , Animais Geneticamente Modificados , Pressão Sanguínea/efeitos dos fármacos , Nefropatias Diabéticas/prevenção & controle , Progressão da Doença , Quimioterapia Combinada , Feminino , Heterozigoto , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Ratos , Valina/análogos & derivados , Valsartana
11.
Mol Cell Endocrinol ; 173(1-2): 203-12, 2001 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-11223191

RESUMO

In Ren-2 rats, plasma active renin and prorenin increase following binephrectomy (BNx) related to increasing plasma potassium. Adrenal is the source of the increasing prorenin but active renin comes mainly from thymus and gut. Trophic influences other than potassium were tested in the present work. Angiotensin did not influence the post-BNx increases in plasma active or prorenin but suppressed resting plasma prorenin from non-adrenal, non-renal sources virtually to zero. ACTH and histamine had no discernible effects. Hexamethonium decreased by 50% the post BNx increase in prorenin but not active renin. In Sprague-Dawley and spontaneously hypertensive rats, low levels of active renin secretion were detected from adrenal but no prorenin. Thus, in anesthetized Ren-2 rats, secreted prorenin is from two sources, i.e. extrarenal and extra-adrenal sites readily suppressible with angiotensin and the adrenal that is partly suppressible by autonomic blockage. This may assist in identifying the origin of extra-renal prorenin secreted in man.


Assuntos
Glândulas Suprarrenais/metabolismo , Precursores Enzimáticos/metabolismo , Renina/metabolismo , Glândulas Suprarrenais/efeitos dos fármacos , Hormônio Adrenocorticotrópico/farmacologia , Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Hipertensivos/farmacologia , Modelos Animais de Doenças , Enalapril/farmacologia , Precursores Enzimáticos/genética , Feminino , Bloqueadores Ganglionares/farmacologia , Dosagem de Genes , Hexametônio/farmacologia , Histamina/farmacologia , Hipertensão/sangue , Hipertensão/genética , Hipertensão/metabolismo , Nefrectomia , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Renina/sangue , Renina/genética , Vasoconstritores/farmacologia
12.
Int Orthop ; 25(6): 378-81, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11820446

RESUMO

We have reviewed 142 Miller-Galante I (MG I) total knee arthroplasties (TKAs) with a follow-up of 56 months, and compared these with the outcome of 219 Miller-Galante II (MG II) TKAs with a follow-up of 36 months. In the MG II TKAs we found markedly lower revision rates, higher postoperative Hospital for Special Surgery (HSS) scores, less retropatellar pain and better patellar centring without patellar resurfacing. The higher revision rate in MG I TKAs was mainly due to the need to revise the metal-backed patellae.


Assuntos
Prótese do Joelho , Artrite/cirurgia , Artroplastia do Joelho , Humanos , Instabilidade Articular/cirurgia , Articulação do Joelho , Desenho de Prótese , Falha de Prótese , Reoperação
13.
Diabetologia ; 43(11): 1360-7, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11126403

RESUMO

AIMS/HYPOTHESIS: Angiotensin converting enzyme (ACE) inhibition has been recently suggested to have retinoprotective actions in diabetic patients but the mechanism of this effect is not known. In vitro, angiotensin II stimulates expression of vascular endothelial growth factor (VEGF), a permeability-inducing and endothelial cell specific angiogenic factor which has been implicated in the pathogenesis of diabetic retinopathy in humans and in experimental animals. We sought to determine the effects of ACE inhibition on retinal VEGF expression and permeability in experimental diabetic retinopathy. METHODS: Streptozotocin-induced diabetic rats and control animals were assigned at random to receive ACE inhibitor treatment or vehicle. At 24 weeks the retinal VEGF protein gene expression was assessed by northern blot analysis and in situ hybridisation. Retinal permeability to albumin was measured using a double isotope technique. RESULTS: Experimental diabetes was associated with cell specific two to fourfold increase in retinal VEGF protein gene expression (p < 0.01) and a 2-fold increase in retinal vascular permeability to albumin (p < 0.01). The localization of VEGF expression in the retina was not altered in animals with experimental diabetes. Angiotensin converting enzyme inhibitor treatment of diabetic rats reduced diabetes-associated changes in VEGF gene expression and vascular permeability. CONCLUSION/INTERPRETATION: These findings implicate the renin-angiotensin system in the VEGF overexpression and hyperpermeability which accompany diabetic retinopathy and provide a potential mechanism for the beneficial effects of ACE inhibition in diabetic retinal disease.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Permeabilidade Capilar/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Fatores de Crescimento Endotelial/genética , Expressão Gênica/efeitos dos fármacos , Linfocinas/genética , Retina/efeitos dos fármacos , Angiotensina II/fisiologia , Animais , Northern Blotting , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/fisiopatologia , Hibridização In Situ , Masculino , Perindopril/farmacologia , RNA Mensageiro/análise , Ramipril/farmacologia , Ratos , Ratos Sprague-Dawley , Retina/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/fisiopatologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
14.
Clin Exp Pharmacol Physiol ; 27(8): 631-3, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10901395

RESUMO

1. Epidemiological studies indicate that a reduced birthweight increases the likelihood of human cardiovascular disease later in life. The role of hormonal factors in this finding is not known. Given that angiotensin II is believed to be a fetal regulator of growth, we have examined in the hypertensive Ren-2 transgenic rat whether it has active renin in its amniotic fluid and whether this is associated with fetal underdevelopment. 2. We found that while the Sprague-Dawley rat contained no active renin in its amniotic fluid near term (20 days), Ren-2 amniotic fluid contains high levels of active renin and is associated with a reduced fetal weight. 3. This is the first report of active renin in the rat and allows the possibility that renin overproduction plays a role in reduced fetal growth and the prenatal 'programming' of essential hypertension that has been proposed to occur in humans.


Assuntos
Líquido Amniótico/metabolismo , Renina/metabolismo , Animais , Animais Geneticamente Modificados , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Precursores Enzimáticos/sangue , Precursores Enzimáticos/genética , Feminino , Camundongos , Gravidez , Ratos , Ratos Sprague-Dawley , Renina/sangue , Renina/genética
15.
Kidney Int ; 57(5): 1882-94, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10792607

RESUMO

BACKGROUND: Endothelin (ET) and angiotensin II (Ang II) are vasoactive/trophic peptides that may contribute to the progression of diabetic nephropathy. The transgenic (mRen-2)27 rat exhibits overexpression of Ang II at sites of normal physiological expression. Unlike other rat strains, the streptozotocin-induced diabetic Ren-2 rat develops progressive renal pathology associated with a declining glomerular filtration rate (GFR) and provides a convenient model to evaluate the role of these vasoactive peptides in the nephropathic process. METHODS AND RESULTS: Oral administration of either the endothelin A (ETA) and ETB receptor antagonist bosentan or the angiotensin type 1 (AT1) receptor antagonist valsartan for 12 weeks reduced systolic blood pressure (SBP) of nondiabetic and diabetic Ren-2 rats to normotensive levels. Diabetic renal pathology was associated with intense renin mRNA and protein in the proximal tubules and juxtaglomerular cells along with overexpression of transforming growth factor-beta1 (TGF-beta1) and collagen IV mRNA in glomeruli and tubules. With valsartan but not bosentan, renin mRNA and protein in the proximal tubules were not detected. Valsartan but not bosentan reduced TGF-beta1 and collagen IV mRNA and the severity of diabetic renal pathology. A declining GFR with diabetes was attenuated by both treatments. Albuminuria in diabetic rats rose further with bosentan but was reduced with valsartan. CONCLUSIONS: Despite producing normotension, severe diabetic renal pathology was not prevented by bosentan, suggesting dissociation of ET, albuminuria, and hypertension from the structural injury in this diabetic model. The beneficial effects afforded by valsartan therapy strengthen the importance of the local renin-angiotensin system in mediating progressive diabetic renal injury.


Assuntos
Antagonistas de Receptores de Angiotensina , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Renina/genética , Animais , Animais Geneticamente Modificados , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal , Colágeno/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Feminino , Imuno-Histoquímica , RNA Mensageiro/análise , Ratos , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Estreptozocina , Fator de Crescimento Transformador beta/fisiologia
16.
Hypertension ; 36(6): 1099-104, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11116132

RESUMO

Both angiotensin II and vascular endothelial growth factor are angiogenic agents that have recently been implicated in the pathogenesis of proliferative diabetic retinopathy. In this study, retinal neovascularization was examined in a model of retinopathy of prematurity with the use of neonatal transgenic (mRen-2)27 rats, which overexpress renin in tissues, and Sprague-Dawley rats. Blockers of the renin-angiotensin system were administered during the neovascularization period. The ACE inhibitor lisinopril and the angiotensin type 1 receptor antagonist losartan both increased retinal renin levels and prevented inner retinal blood vessel growth. Quantitative in situ hybridization revealed that the expression of vascular endothelial growth factor and its type 2 receptor in the inner retina and proliferating blood vessels were increased in rats with retinopathy of prematurity. Lisinopril reduced both retinal vascular endothelial growth factor and its type 2 receptor mRNA in retinopathy of prematurity rats, whereas losartan had no effect. It is predicted that agents that interrupt the renin-angiotensin system may play an important role as retinoprotective agents in various forms of proliferative retinopathy.


Assuntos
Sistema Renina-Angiotensina/fisiologia , Neovascularização Retiniana/prevenção & controle , Retinopatia da Prematuridade/fisiopatologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Animais Geneticamente Modificados , Animais Recém-Nascidos , Modelos Animais de Doenças , Fatores de Crescimento Endotelial/fisiologia , Humanos , Hibridização In Situ , Recém-Nascido , Lisinopril/farmacologia , Linfocinas/fisiologia , Ratos , Ratos Sprague-Dawley , Renina/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , Retina/metabolismo , Neovascularização Retiniana/metabolismo , Retinopatia da Prematuridade/patologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
17.
Electrophoresis ; 21(1): 135-49, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10634480

RESUMO

In this paper we present the development of a DNA analysis system using a microfabricated channel device and a novel transmission imaging spectrograph which can be efficiently incorporated into a high throughput genomics facility for both sizing and sequencing of DNA fragments. The device contains 48 channels etched on a glass substrate. The channels are sealed with a flat glass plate which also provides a series of apertures for sample loading and contact with buffer reservoirs. Samples can be easily loaded in volumes up to 640 nL without band broadening because of an efficient electrokinetic stacking at the electrophoresis channel entrance. The system uses a dual laser excitation source and a highly sensitive charge-coupled device (CCD) detector allowing for simultaneous detection of many fluorescent dyes. The sieving matrices for the separation of single-stranded DNA fragments are polymerized in situ in denaturing buffer systems. Examples of separation of single-stranded DNA fragments up to 500 bases in length are shown, including accurate sizing of GeneCalling fragments, and sequencing samples prepared with a reduced amount of dye terminators. An increase in sample throughput has been achieved by color multiplexing.


Assuntos
DNA/análise , DNA/genética , Eletroforese/métodos , Análise de Sequência de DNA/métodos , Animais , Sequência de Bases , Humanos , Processamento de Imagem Assistida por Computador , Dados de Sequência Molecular
18.
Am J Physiol ; 277(4): E639-46, 1999 10.
Artigo em Inglês | MEDLINE | ID: mdl-10516123

RESUMO

Thymic ablation and assay of organ renin revealed that one-third of the increasing plasma level of active renin after removal of kidneys and adrenals from Ren-2 rats originates from the thymus. Splanchnic arteriovenous difference and renin content indicate that gut can account for the remainder. Secretion of active renin from these sites correlated significantly with increasing plasma potassium. Prorenin was not secreted from these sites or from hindlimb in amounts sufficient to raise the plasma level, and yet plasma prorenin remained higher than active renin throughout the 12-h protocol. The source of prorenin that accounts for the high plasma prorenin phenotype of the intact conscious Ren-2 rat was not specifically identified. When sensitive assays were used, a low level of active renin secretion from thymus and gut was also apparent 12 h after removal of kidneys and adrenals in normal Sprague-Dawley rats, and plasma prorenin was at this time higher than active renin. A likely source of this extrarenal, extra-adrenal renin is the macrophage.


Assuntos
Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Renina/metabolismo , Glândulas Suprarrenais/metabolismo , Animais , Feminino , Membro Posterior/metabolismo , Mucosa Intestinal/metabolismo , Ratos , Ratos Sprague-Dawley/metabolismo , Timo/metabolismo , Distribuição Tecidual
19.
Am J Physiol ; 277(4): E631-8, 1999 10.
Artigo em Inglês | MEDLINE | ID: mdl-10516122

RESUMO

Plasma active renin and prorenin were followed for 12 h after bilateral, unilateral, and sham nephrectomy (BNx, UNx, and SNx) in anesthetized transgenic (mRen-2)27 rats to compare them with Sprague-Dawley and spontaneously hypertensive rats (SDR and SHR). In Ren-2 rats, active renin and prorenin increased with plasma potassium post-BNx and were augmented by potassium infusion. The increase in prorenin but not active renin was abolished by bilateral adrenalectomy (BADRx). However, this did not reduce prorenin below normal, indicating that the high plasma prorenin Ren-2 phenotype is not only of adrenal origin. SNx and UNx also raised plasma active renin and prorenin in Ren-2 rats, with positive correlations to plasma potassium. In SDR and SHR, active renin fell below prorenin post-BNx, and adrenal ablation and potassium loading (in SDR) modified the decreasing active renin profile consistent with low levels of regulated extrarenal secretion. In Ren-2 rats, adrenal but not extra-adrenal prorenin secretion is potassium sensitive and stress related. The unidentified source of active renin in BNx+BADRx Ren-2 rats is also potassium and stress related.


Assuntos
Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Potássio/fisiologia , Renina/metabolismo , Adrenalectomia , Animais , Precursores Enzimáticos/sangue , Hipertensão/sangue , Camundongos , Nefrectomia/métodos , Período Pós-Operatório , Potássio/sangue , Potássio/farmacologia , Ratos , Ratos Endogâmicos SHR/sangue , Ratos Endogâmicos , Ratos Sprague-Dawley/sangue , Valores de Referência , Renina/sangue
20.
Am J Pathol ; 155(2): 429-40, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10433936

RESUMO

The finding that the systemic renin-angiotensin system (RAS) is not activated in most types of chronic renal disease has led to the suggestion that a local, intrarenal RAS may be an important determinant in the relentless progression of renal disease. Therefore, cell specific changes in various components of the RAS in response to renal mass reduction and angiotensin converting enzyme (ACE) inhibition were examined. Thirty Sprague-Dawley rats were randomly assigned to sham surgery, subtotal nephrectomy (STNx) alone or STNx treated with the ACE inhibitor, perindopril, and sacrificed after 12 weeks. In sham rats, renin mRNA and protein were only present in the juxtaglomerular apparatus. In contrast, in STNx kidneys, renin and angiotensin II expression were noted predominantly in renal tubular epithelial cells in association with overexpression of the prosclerotic cytokine, transforming growth factor-beta1 (TGF-beta1). In perindopril-treated STNx rats expression of renin and TGF-beta1 were similar to control animals. These finding indicate that following renal mass reduction there is pathological tubular expression of various components of the RAS. Furthermore, in contrast to the juxtaglomerular apparatus, tubular renin expression was reduced with ACE inhibition. These changes within the intrarenal RAS may be pathogenetically linked to the development of tubulointerstitial injury.


Assuntos
Angiotensina II/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/cirurgia , Nefrectomia , Nefrite Intersticial/metabolismo , Renina/metabolismo , Angiotensina II/análise , Animais , Colágeno/análise , Colágeno/metabolismo , Imuno-Histoquímica , Hibridização In Situ , Rim/anatomia & histologia , Rim/patologia , Rim/cirurgia , Túbulos Renais/anatomia & histologia , Masculino , Peptidil Dipeptidase A/análise , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Renina/análise , Fator de Crescimento Transformador alfa/análise , Fator de Crescimento Transformador alfa/metabolismo , Fator de Crescimento Transformador beta/análise , Fator de Crescimento Transformador beta/metabolismo
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