RESUMO
BACKGROUND AND OBJECTIVE: In subtotally nephrectomized rats, we studied to what extent high-dose calcitriol-induced cardiovascular disease can be modulated by almost complete suppression of parathyroid hormone (PTH), mediated by either cinacalcet (CINA) or parathyroidectomy (PTX). METHODS: Five groups were studied: sham-operated controls, uremic (U), uremic with calcitriol (U+1,25D), uremic and calcitriol with CINA (U+1,25D+CINA) and uremic and calcitriol with PTX (U+1,25D+PTX). Treatments lasted 14 weeks. RESULTS: Compared with U group animals, PTH was significantly lower with calcitriol treatment and almost completely suppressed in animals treated with either PTX or CINA. Serum calcium and phosphorus levels were similarly elevated in all groups receiving calcitriol. Renal function in uremic animals was significantly more impaired in the U+1,25D group. Aortic calcifications were pronounced in U+1,25D animals and reduced by more than 50% by concomittant treatment with CINA or PTX. Chondrocytes were observed near areas of calcification (>90%) and endochondral bone formation was confirmed by positive immunofluorescence for chondrocytic transcription factor sox9 and matrix protein collagen X. Altered arterial (aneurysmatic) geometry with a significant increase in wall/lumen and lumen/body weight ratio was found only in the U+1,25D group. Myocardial fibrosis was present in all uremic groups with a significant increase in the U+1,25D group. Connective tissue growth factor messenger RNA was significantly upregulated only in the U+1,25D group. CONCLUSION: Submaximal suppression of PTH by either CINA or PTX reduced vascular calcifications, arterial remodeling and myocardial fibrosis to a similar degree and independent of the serum calcium and phosphorus levels. These data do not indicate vasculotropic effects of calcimimetics independent of PTH suppression.
Assuntos
Hormônio Paratireóideo/antagonistas & inibidores , Uremia/patologia , Uremia/terapia , Animais , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Doenças da Aorta/terapia , Sequência de Bases , Calcinose/etiologia , Calcinose/patologia , Calcinose/terapia , Calcitriol/toxicidade , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/terapia , Cinacalcete , Fator de Crescimento do Tecido Conjuntivo/genética , Fibrose , Masculino , Naftalenos/farmacologia , Nefrectomia , Paratireoidectomia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Uremia/complicaçõesRESUMO
PURPOSE: Gender difference and nitric oxide deficiency contribute to the progression of many chronic kidney diseases. In a model of unilateral ureteral obstruction relief we analyzed the impact of biological gender and nitric oxide/cyclic guanosine monophosphate signaling stimulation on renal disease severity and restoration. MATERIALS AND METHODS: Female and male rats underwent sham surgery or unilateral ureteral obstruction. After 5-day unilateral ureteral obstruction female and male rats were assigned to obstruction relief alone or obstruction relief plus 7-day treatment with the soluble guanylate cyclase stimulator BAY 41-8543. RESULTS: Compared to male rats with obstruction relief renal disease was less severe in female rats, which had significantly less tubulointerstitial matrix accumulation and tubular atrophy. In each gender group α1 and ß1-soluble guanylate cyclase was comparably and significantly increased but female rats produced significantly more cyclic guanosine monophosphate after treatment with the soluble guanylate cyclase stimulator. In each group BAY 41-8543 treatment was associated with significant amelioration of renal matrix protein expansion, macrophage infiltration, tubular apoptosis and atrophy. CONCLUSIONS: Female gender is protective for unilateral ureteral obstruction relief. This was linked to higher sensitivity of the soluble guanylate cyclase enzyme and cyclic guanosine monophosphate production in response to BAY 41-8543. In these female and male rats enhancing the signaling of nitric oxide/cyclic guanosine monophosphate with BAY 41-8543 significantly accelerated the restoration of renal architecture after obstruction relief and largely ameliorated the differences in disease severity due to the gender disparity.
Assuntos
Regulação da Expressão Gênica , Guanilato Ciclase/genética , Rim/fisiologia , Morfolinas/uso terapêutico , Pirimidinas/uso terapêutico , RNA Mensageiro/genética , Receptores Citoplasmáticos e Nucleares/genética , Recuperação de Função Fisiológica , Obstrução Ureteral/tratamento farmacológico , Administração Oral , Animais , Apoptose , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Guanilato Ciclase/biossíntese , Marcação In Situ das Extremidades Cortadas , Masculino , Morfolinas/administração & dosagem , Pirimidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/biossíntese , Índice de Gravidade de Doença , Fatores Sexuais , Guanilil Ciclase Solúvel , Resultado do Tratamento , Obstrução Ureteral/patologia , Obstrução Ureteral/fisiopatologiaRESUMO
Rosuvastatin is additive to high-dose candesartan in slowing progression of experimental mesangioproliferative glomerulosclerosis (GS). Progressive mesangioproliferative glomerulonephritis, mostly IgA nephropathy, is a major cause of end-stage kidney disease worldwide. In a chronic-progressive model of mesangioproliferative GS, we tested the renoprotective efficacy of rosuvastatin alone and in combination with a high-dose of the AT(1) blocker candesartan. Treatment was started 1 wk after disease induction (anti-thy1 antibody injection into uninephrectomized rats) and continued until week 20. Tubulointerstitial expression of the key fibrosis mediator transforming growth factor (TGF)-beta served as the main marker of disease progression. Compared with the untreated GS rats (475 +/- 52 pg/ml), tubulointerstitial TGF-beta(1) protein expression was significantly reduced by both single therapies (rosuvastatin -47%, candesartan -51%, P < 0.01). Tubulointerstitial matrix accumulation (matrix score in GS: 64 +/- 7%) was relatively reduced by -45 and -52%, respectively (P < 0.01). The combination of rosuvastatin and candesartan had significantly greater effects on tubulointerstitial TGF-beta(1) expression (-82% vs. GS) and matrix accumulation (-83% vs. GS) (P < 0.001 vs. GS, P < 0.05 vs. single therapy) than either drug alone. Similar additive beneficial effects were observed for renal fibronectin and tissue inhibitor of metalloproteinase-1 expression, cell proliferation, macrophage infiltration, proteinuria, and kidney function. In conclusion, rosuvastatin limits the progressive course of anti-thy1-induced GS toward chronic tubulointerstitial fibrosis and renal insufficiency to a degree comparable to the one achieved by a high dose of the AT(1) antagonist candesartan. Combined treatment yields significantly greater actions on renal TGF-beta overexpression and matrix accumulation, cell proliferation, and macrophage infiltration. The results suggest that rosuvastatin and an AT(1) blocker independently interfere with separate key pathways involved in the progression of chronic mesangioproliferative GS.
Assuntos
Benzimidazóis/uso terapêutico , Fluorbenzenos/uso terapêutico , Glomerulosclerose Segmentar e Focal/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Tetrazóis/uso terapêutico , Animais , Compostos de Bifenilo , Modelos Animais de Doenças , Progressão da Doença , Quimioterapia Combinada , Glomerulosclerose Segmentar e Focal/fisiopatologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Masculino , Proteinúria/prevenção & controle , Ratos , Ratos Wistar , Rosuvastatina CálcicaRESUMO
Chronic kidney diseases frequently advance to end-stage renal failure, and the number of patients affected is steadily increasing worldwide. At the molecular level, progression of renal insufficiency correlates closely with ongoing pathological matrix protein expansion (i.e., renal fibrosis), in a manner independent of the underlying disorder. Overactivity of the renin-angiotensin system and of the TGF-beta system have been identified as key mediators of kidney matrix accumulation, and are principal targets in the management of chronic renal disease. This review provides a recent overview of the therapeutic options that are clinically established, and of novel molecular strategies that will approach clinical practice in the near future.
Assuntos
Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Angiotensina II/antagonistas & inibidores , Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Fibrose , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Guias de Prática Clínica como Assunto , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismoRESUMO
Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg.kg body wt(-1).day(-1)), cGS plus high-dose enalapril (12 mg.kg body wt(-1).day(-1)), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-beta(1), fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high-dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Enalapril/uso terapêutico , Imunossupressores/uso terapêutico , Nefropatias/tratamento farmacológico , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacologia , Antígenos Thy-1/imunologia , Animais , Contagem de Células Sanguíneas , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Progressão da Doença , Interações Medicamentosas , Ingestão de Alimentos/fisiologia , Fibronectinas/metabolismo , Fibrose , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Imuno-Histoquímica , Nefropatias/patologia , Testes de Função Renal , Masculino , Nefrectomia , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Proteinúria/tratamento farmacológico , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1RESUMO
BACKGROUND: The Genius dialysis system is a close loop dialysis batch system increasingly used as an intermittent hemodialysis device in intensive care units. The aim of this study was to test the safety and feasibility of a regional citrate anticoagulation protocol with respect to acid-base and electrolyte disarrangements in critically ill patients with acute renal failure. A standard heparin anticoagulation protocol served as control. METHODS AND RESULTS: In a cross-over study design, 27 acute renal failure patients were allocated to a citrate- and heparin-anticoagulated dialysis sessions (4-6 h). For citrate anticoagulation, a 4% sodium-citrate solution was infused into the arterial line of the extracorporeal circuit. A low calcium dialysate (1 mmol/l) was used for all dialysis sessions. Citrate dosing was adjusted according to the post-filter ionized calcium concentration (targeted values 0.5-0.7 mmol/l). There was no routine calcium substitution. Heparin anticoagulation was started with a heparin-loading dose followed by an individual, patient-adjusted continuous heparin infusion. Electrolyte disarrangements, namely hypernatremia, hypo- and hypercalcemia did not occur in either group. Although the highest bicarbonate levels were achieved during citrate anticoagulation (p = 0.021 versus heparin) the acid base values remained equilibrated in both groups. Filter longevity was excellent and the targeted dialysis time was achieved in all but 1 patient. Citrate anticoagulation was well tolerated with respect to cardiovascular hemodynamics. CONCLUSIONS: Citrate anticoagulation can be safely and effectively performed during intermittent Genius dialysis. Calcium supplementation is not routinely required.
Assuntos
Injúria Renal Aguda/terapia , Anticoagulantes/administração & dosagem , Citratos/administração & dosagem , Heparina/administração & dosagem , Diálise Renal/métodos , Equilíbrio Ácido-Base , Injúria Renal Aguda/metabolismo , Protocolos Clínicos , Estudos Cross-Over , Humanos , Pessoa de Meia-IdadeRESUMO
UNLABELLED: NO mediates antifibrotic actions of L-arginine supplementation following induction of anti-thy1 glomerulonephritis. BACKGROUND: L-Arginine plays a complex role in renal matrix expansion, involving endogenous metabolism into nitric oxide (NO), polyamines, L-proline and agmatine. Supplementing dietary L-arginine intake has been shown to limit transforming growth factor (TGF)-beta 1 overproduction and matrix accumulation in rats with induced anti-thy1 glomerulonephritis (GN). The present study tests the hypothesis that this beneficial effect on in vivo TGF-beta overexpression is mediated via the generation of NO. METHODS: One day after induction of anti-thy1 GN, male Wistar rats fed a normal protein diet were assigned to the following groups: (1) normal controls; (2) GN; (3) GN-Arg (plus 500 mg L-arginine/day); (4) GN-Arg-NAME [plus 500 mg L-arginine/day and 75 mg/L of the NO synthase inhibitor nitro-L-arginine-methyl ester (L-NAME) in the drinking water]; and (5) GN-Molsi (10 mg/day of the NO donor molsidomine). In protocol 1, treatment lasted until day 7, and in protocol 2, until day 12 after disease induction, respectively. Analysis included systolic blood pressure, a glomerular histologic matrix score, and the glomerular mRNA and protein expression of the key fibrogen TGF-beta1, the matrix protein fibronectin, and the protease inhibitor plasminogen activator inhibitor type 1 (PAI-1). RESULTS: Blood pressure was normal in untreated anti-thy1 animals and not significantly affected by any of the treatments. Compared to untreated nephritic rats, administration of both L-arginine and molsidomine reduced glomerular TGF-beta 1 overexpression significantly and to a similar degree in both protocols, while the beneficial effect of L-arginine was abolished by concomitant NO synthesis inhibition. Glomerular matrix accumulation, fibronectin and PAI-1 mRNA and protein expression closely followed the expression of TGF-beta 1. CONCLUSION: The present study shows that L-arginine's antifibrotic action in normotensive anti-thy1 GN is mainly mediated by endogenous production of NO. The data suggest that NO limits in vivo TGF-beta overexpression in a pressure-independent manner and that NO donors may be of benefit in the treatment of human fibrotic renal disease.
Assuntos
Arginina/farmacologia , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/metabolismo , Óxido Nítrico/metabolismo , Animais , Pressão Sanguínea , Peso Corporal , Inibidores Enzimáticos/farmacologia , Fibronectinas/genética , Fibrose , Expressão Gênica , Glomerulonefrite/patologia , Isoanticorpos/farmacologia , Masculino , Molsidomina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Nitratos/sangue , Doadores de Óxido Nítrico/farmacologia , Nitritos/sangue , Inibidor 1 de Ativador de Plasminogênio/genética , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , Proteinúria/patologia , RNA Mensageiro/análise , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta1RESUMO
OBJECTIVE: Recent experimental studies in chronic kidney disease have suggested that sympathicolytic drugs, similar to angiotensin II antagonism, limit renal fibrosis independent of blood pressure control. Using the model of acute and normotensive anti-thy1 glomerulonephritis, we analysed the action of beta-adrenergic blockade (as compared with angiotensin-converting enzyme inhibition) on renal overexpression of the profibrotic cytokine transforming growth factor (TGF)-beta. METHODS: One day after induction of anti-thy1 glomerulonephritis, rats were given increasing doses of the beta-blockers metoprolol or nebivolol (0.1-fold, one-fold, 10-fold and 20-fold of the known blood pressure dose) until day 6 and the 20-fold dose until day 12. Additional animals were treated with a high dose of the angiotensin-converting enzyme inhibitor enalapril. At the end of each experiment, blood pressure and heart rate were recorded, glomerular matrix expansion was scored histologically, and protein expression of TGF-beta(1), fibronectin and plasminogen activator inhibitor-1 was determined in the supernatant of cultured glomeruli. RESULTS: Metoprolol and nebivolol reduced heart rate in a dose-dependent manner. Blood pressure was normal in untreated animals and not significantly affected by either treatment. Compared with untreated nephritic rats, TGF-beta(1) overexpression was not significantly changed by metoprolol or nebivolol in any dose or treatment period. In contrast, TGF-beta(1) levels were significantly reduced by enalapril both 6 and 12 days after disease induction (-52 and -63%, respectively). The changes in glomerular matrix score, fibronectin and plasminogen activator inhibitor-1 production closely followed expression of TGF-beta(1). CONCLUSIONS: In a model of acute and normotensive glomerular fibrosis, beta-adrenergic antagonism does not reduce TGF-beta overexpression, suggesting that its pressure-independent antifibrotic action may be limited to chronic renal diseases. The beneficial effect of angiotensin II inhibition even on acute matrix expansion may be a relevant mechanism as to the explanation of its superiority in treating fibrotic renal diseases.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Enalapril/farmacologia , Glomerulonefrite/tratamento farmacológico , Metoprolol/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Benzopiranos/farmacologia , Biomarcadores , Pressão Sanguínea , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Etanolaminas/farmacologia , Fibrose , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Frequência Cardíaca , Isoanticorpos , Masculino , Nebivolol , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta1RESUMO
BACKGROUND: Inducible, high-output nitric oxide (NO) production has been identified as a central mediator of cell injury in immune-mediated renal disease. In acute anti-thy-1 glomerulonephritis prefeeding with the NO precursor L-arginine increases mesangial cell injury and the subsequent fibrosis. The present study tested the hypothesis that L-arginine supplementation may also be detrimental in chronic, NO-mediated murine lupus nephritis. METHODS: Groups (N = 18) of female MRL/lpr mice with lupus nephritis were fed the following diets: (1) normal protein (22% casein); (2) normal protein and 1.0% L-arginine in the drinking water; (3) low protein (6% casein); (4) low protein + 0.4%l-arginine; and (5) low protein + 1.0% L-arginine. After 40 days mouse survival, albuminuria, matrix accumulation, inflammatory cell infiltration, immunoglobulin G (IgG) deposition, expression of transforming growth factor-beta 1 (TGF-beta 1), fibronectin and plasminogen activator inhibitor-1 (PAI-1) mRNA and protein, anti-DNA antibody titer, inducible nitric oxide synthase (iNOS) mRNA expression, blood amino acid levels, blood urea nitrogen (BUN) concentrations and blood and urinary NOx (nitrite + nitrate) levels were assessed. RESULTS: L-Arginine supplementation increased mortality significantly (P < 0.02). The death rate increased from 0% in the lowest to 50% in the highest L-arginine intake group (normal protein + 1.0% L-arginine). L-Arginine administration increased albuminuria, renal matrix accumulation, TGF-beta 1, fibronectin, PAI-1, blood L-arginine, L-citrulline, BUN and blood and urine NOx levels, while protein restriction reduced these parameters. Renal cell infiltration and iNOS mRNA expression were decreased in the low protein group only. Anti-ds DNA-IgG and renal IgG deposition were comparable in all groups CONCLUSIONS: Increasing L-arginine intake increases the severity of renal fibrosis and the likelihood of death in MRL/lpr mice. The results appear to be at least in part mediated through enhanced cytotoxic NO generation via iNOS. The data suggest that L-arginine restriction should be considered in human immune-mediated renal diseases.