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1.
Contemp Clin Trials Commun ; 15: 100365, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31193611

RESUMO

Background: Elderly maintenance hemodialysis (MHD) patients exhibit muscle wasting and impaired physical function. This trial determines whether MHD patients benefit from a 12-week home-based exercise program, protein supplementation, or both. Design: and Methods: This is a randomized, blinded controlled trial involving 60 elderly MHD patients with impaired exercise capacity and function. Patients are randomized into either a homebased exercise program or normal care over a 12-week period. Measures at baseline include peak VO2, strength and body composition as well as cognitive and disease-specific questionnaires. Muscle biopsies are obtained and analyzed for protein signaling, expression of IGF-1, androgen receptors, and myostatin. Results: At baseline, patient characteristics in the exercise and normal care groups were similar by age, gender and anthropomorphic measures. Peak VO2 was impaired (14.7 ±â€¯3.3 ml/kg/min), representing 55 ±â€¯14% of the age-predicted value. Six-minute walk distance was 322 ±â€¯71 m, and the mean 1-min sit to stand test was 18 ±â€¯8 repetitions, representing 69 ±â€¯16% and 55 ±â€¯22% of the age-predicted values, respectively. Indices of muscle function, including upper and lower body and hand grip strength all indicate marked impairment. Quality of life (QoL) using the SF36, the Beeson cognitive test, and KDQOL all suggest marked impairments compared to age-expected reference values for non-MHD patients. Conclusions: Patients undergoing MHD exhibit markedly reduced physical function and QoL. Thus, there are potentially significant gains to be made through a program of aerobic and resistance exercise. We anticipate this trial will demonstrate that home-based exercise improves cardiopulmonary function, protein signaling and QoL, and increases muscle mass, strength, and body composition.

2.
Clin Transplant ; 31(8)2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28564126

RESUMO

Many patients become frail with diminished cardiorespiratory fitness while awaiting kidney transplantation. Frailty and poor fitness powerfully predict mortality, transplant graft survival, and healthcare utilization after kidney transplantation. Efforts to intervene with post-transplant physical therapy have been met with limited success, in large part due to high study dropout. We reviewed the literature on chronic kidney disease and exercise to propose a clinical framework for physical therapy interventions to improve fitness, scheduled for before the transplant. This framework may lead to better patient retention and compliance, and thus demonstrate better efficacy in mitigating the effects of frailty and poor fitness after kidney transplantation.


Assuntos
Falência Renal Crônica/reabilitação , Transplante de Rim , Modalidades de Fisioterapia , Cuidados Pré-Operatórios/métodos , Teste de Esforço , Fragilidade , Humanos , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/cirurgia , Aptidão Física
3.
Nephrol Dial Transplant ; 31(8): 1270-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26560811

RESUMO

BACKGROUND: Childhood chronic kidney disease (CKD) is associated with both short stature and abnormal bone mineralization. Normal longitudinal growth depends on proper maturation of epiphyseal growth plate (EGP) chondrocytes, leading to the formation of trabecular bone in the primary ossification centre. We have recently shown that linear growth impairment in CKD is associated with impaired EGP growth hormone (GH) receptor signalling and that exercise improved insulin-like growth factor I (IGF-I) signalling in CKD-related muscle atrophy. METHODS: In this study, 20-day-old rats underwent 5/6 nephrectomy (CKD) or sham surgery (C) and were exercised with treadmill, with or without GH supplementation. RESULTS: CKD-related growth retardation was associated with a widened EGP hypertrophic zone. This was not fully corrected by exercise (except for tibial length). Exercise in CKD improved the expression of EGP key factors of endochondral ossification such as IGF-I, vascular endothelial growth factor (VEGF), receptor activator of nuclear factor kappa-B ligand (RANKL) and osteocalcin. Combining GH treatment with treadmill exercise for 2 weeks improved the decreased trabecular bone volume in CKD, as well as the expression of growth plate runt-related transcription factor 2, RANKL, metalloproteinase 13 and VEGF, while GH treatment alone could not do that. CONCLUSIONS: Treadmill exercise improves tibial bone linear growth, as well as growth plate local IGF-I. When combined with GH treatment, running exercise shows beneficial effects on trabecular bone formation, suggesting the potential benefit of this combination for CKD-related short stature and bone disease.


Assuntos
Osso e Ossos/citologia , Transtornos do Crescimento/terapia , Hormônio do Crescimento/administração & dosagem , Osteogênese/efeitos dos fármacos , Condicionamento Físico Animal , Insuficiência Renal Crônica/terapia , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Terapia Combinada , Transtornos do Crescimento/fisiopatologia , Masculino , Osteogênese/fisiologia , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/fisiopatologia
4.
Am J Nephrol ; 40(4): 362-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25358492

RESUMO

BACKGROUND: Critical illnesses are often complicated by acute metabolic acidosis, which if persistent, adversely affects outcome. Among the harmful effects that it might cause are impaired utilization of nutrients, increased proteolysis and depressed protein synthesis, leading to muscle wasting. As the amino acid leucine stimulates protein synthesis by activating mTOR signaling, we explored whether in acidosis, impaired leucine-stimulated signaling might be a contributor to the depressed protein synthesis. METHODS: Male pair-fed rats were gavaged with NH4Cl (acidosis) or NaCl (control) for 2 days and then gavaged once with leucine and sacrificed 45 min later. Extensor digitorum longus muscles were isolated, incubated with or without leucine and protein synthesis measured. The anterior tibial muscle signaling was analysed by Western immunobloting. RESULTS: Despite pair-feeding, acidotic rats lost body and muscle weight vs. controls. Moreover, leucine-induced protein synthesis in isolated muscle from acidotic rats was impaired. In-vivo, 45 min after an oral leucine load, anterior tibial muscle mTOR and 4E-BP1 phosphorylation increased significantly and comparably in control and acidotic rats. In contrast, leucine-stimulated phosphorylation of S6K1, a regulator of translation initiation and protein synthesis, was attenuated to approximately 56% of the control value (p < 0.05). CONCLUSION: This study reveals that an acute metabolic acidosis impairs leucine-stimulated protein synthesis and activation of signaling downstream of mTOR at the level of S6K1. We propose that this S6K1 abnormality may account in part, for the resistance to leucine-stimulated muscle protein synthesis, and may thereby contribute to the impaired nutrient utilization and ultimately the muscle wasting that develops in acidosis.


Assuntos
Acidose/metabolismo , Leucina/sangue , Músculo Esquelético/metabolismo , Biossíntese de Proteínas , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Peso Corporal , Insulina/sangue , Masculino , Ratos Sprague-Dawley , Transdução de Sinais
5.
Nephrol Dial Transplant ; 29(4): 791-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24463190

RESUMO

BACKGROUND: Treatment with recombinant human growth hormone (GH) is the standard therapy for short stature in children with chronic kidney disease (CKD). However, concerns have been raised on the potential renal fibrogenic effects of GH. There is no information regarding the renal GH receptor (GHR)-JAK-STAT signaling pathway in CKD. METHODS: Subtotal nephrectomized (CKD) and pair-fed sham-operated control (C) juvenile rats were treated with subcutaneous GH or saline for 2 weeks. A single intravenous GH bolus or vehicle was provided prior to euthanasia. RESULTS: Reduced body weight in CKD was improved with GH therapy. The remnant kidney showed glomerular hypertrophy and early interstitial fibrosis without inflammatory infiltration. Treatment of CKD rats with GH did not worsen renal function or fibrosis. Kidney GHR mRNA and protein levels were reduced and basal phosphorylation of JAK2 and STAT5 was significantly impaired. However, intravenous GH administration prior to sacrifice normalized STAT5 phosphorylation. Basal renal IL6 mRNA and phosphorylation of its downstream signaling molecule STAT3 were increased as was the product of its action, the suppressor of cytokine signaling 3 (SOCS3) mRNA. CONCLUSIONS: Despite known unaltered circulating GH levels, remnant kidneys of uremic growth retarded juvenile rats show impaired basal signaling along the GH-activated JAK2/STAT5 signaling pathway. This may well be a consequence of the reduced GHR level and the inhibitory effect of the increase in IL-6-mediated SOCS3 expression. This renal GH insensitivity, if present in humans, may protect against the potential adverse renal effects of GH administration in CKD patients.


Assuntos
Regulação da Expressão Gênica , Hormônio do Crescimento Humano/administração & dosagem , Janus Quinase 2/genética , Rim/metabolismo , RNA Mensageiro/genética , Insuficiência Renal Crônica/genética , Fator de Transcrição STAT5/genética , Adolescente , Animais , Western Blotting , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Injeções Intravenosas , Interleucina-6/metabolismo , Janus Quinase 2/biossíntese , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Fator de Transcrição STAT5/biossíntese , Transdução de Sinais/efeitos dos fármacos
6.
Kidney Int ; 85(2): 374-82, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23783244

RESUMO

Adequate nutrient intake in acute uremia is a key part of patient management especially as food utilization is usually impaired. Leucine is important as it comprises about one-fifth of essential amino acid needs and, apart from serving as a substrate, it directly activates the mTOR signaling pathway stimulating protein synthesis and inhibiting autophagy. Here we tested whether leucine activation of the mTOR signaling pathway in muscle is severely disrupted in acute uremia. Several abnormalities were identified in bilateral ureteral ligated (model of acute uremia) compared to sham-operated pair-fed control rats. Levels of several signaling proteins increased significantly while leucine-induced phosphorylation of mTOR and downstream proteins, 4e-BP1 and S6K1, was completely suppressed. Levels of LC3B-II, a specific autophagosomal membrane-associated protein used as a marker of autophagy, increased threefold in uremia. Furthermore, while leucine suppressed LC3B-II levels in controls, it failed to do so in uremic rats. Muscle IL-6 mRNA levels increased, while IGF-1 mRNA levels decreased in uremia. These findings establish that, in acute uremia, severe resistance to leucine-induced activation of the mTOR anabolic signaling pathway develops. Thus, leucine resistance, together with the reduction in IGF-1 and increase in IL-6 expression, may explain why the anabolic effect of nutritional therapy is diminished in acute uremic patients.


Assuntos
Lesão Renal Aguda/metabolismo , Leucina/metabolismo , Músculo Esquelético/metabolismo , Transdução de Sinais , Uremia/metabolismo , Doença Aguda , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/genética , Lesão Renal Aguda/fisiopatologia , Animais , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Ligadura , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Estado Nutricional , Fosfoproteínas/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Uremia/etiologia , Uremia/genética , Uremia/fisiopatologia , Ureter/cirurgia
7.
Kidney Int ; 84(5): 940-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23715123

RESUMO

Linear growth retardation in children with chronic kidney disease (CKD) has been ascribed to insensitivity to growth hormone. This resistance state has been attributed to impaired growth hormone signaling through the JAK2/STAT5 pathway in liver and skeletal muscle leading to reduced insulin-like growth factor-I (IGF-I). Here we determine whether systemic and growth plate alterations in growth hormone signaling contribute to CKD-induced linear growth retardation using partially nephrectomized and pair-fed control 20-day-old rats. Serum growth hormone did not change in rats with CKD, yet serum IGF-I levels were decreased and growth retarded. The tibial growth plate hypertrophic zone was wider and vascularization at the primary ossification center was reduced in CKD. This was associated with a decrease in growth plate vascular endothelial growth factor (VEGF) mRNA and immunostainable VEGF and IGF-I levels. Growth plate growth hormone receptor and STAT5 protein levels were unchanged, while JAK2 was reduced. Despite comparable growth hormone and growth hormone receptor levels in CKD and control rats, relative STAT5 phosphorylation was significantly depressed in CKD. Of note, the mRNA of SOCS2, an inhibitor of growth hormone signaling, was increased. Thus, linear growth impairment in CKD can in part be explained by impaired long bone growth plate growth hormone receptor signaling through the JAK2/STAT5 pathway, an abnormality that may be caused by an increase in SOCS2 expression.


Assuntos
Transtornos do Crescimento/etiologia , Hormônio do Crescimento/metabolismo , Lâmina de Crescimento/metabolismo , Insuficiência Renal Crônica/complicações , Transdução de Sinais , Tíbia/metabolismo , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/fisiopatologia , Hormônio do Crescimento/sangue , Lâmina de Crescimento/irrigação sanguínea , Lâmina de Crescimento/crescimento & desenvolvimento , Fator de Crescimento Insulin-Like I/metabolismo , Janus Quinase 2/metabolismo , Rim/fisiopatologia , Masculino , Nefrectomia , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Tíbia/irrigação sanguínea , Tíbia/crescimento & desenvolvimento , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Growth Horm IGF Res ; 21(5): 279-84, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21862442

RESUMO

OBJECTIVE: Increase in kidney IGF-I levels due to its increased trapping from the circulation was hypothesized to be a key mediator of compensatory renal enlargement. We tested this hypothesis using genetically engineered mice with extremely low circulating IGF-I levels. DESIGN: Both IGF-I deficient (ID) and normal (N) mice underwent a uninephrectomy (UNx) and sacrificed 2 or 9days later. RESULTS: Initial body weight (BW) and kidney weight (KW) were significantly reduced in ID vs. N mice, while KW/BW ratios were similar. KW increased post-UNx to a comparable extent in ID and N mice (125±4 and 118±6% of pre-UNx KW, p<0.05 vs. C). Kidney IGF-I mRNA levels were similar in the ID and N mice and did not change post-UNx. Kidney IGF-I peptide levels pre-UNx were significantly lower in ID vs. N mice (25±5 vs. 305±39ng/g) and increased in both groups after UNx, remaining low in ID mice (45±4 in ID vs 561±64ng/g in N). IGF type 1 receptor phosphorylation was unchanged. CONCLUSION: While a severe deficiency of circulating IGF-I impairs body growth, UNx induces a significant and proportional increase in renal mass in ID mice despite markedly decreased kidney IGF-I levels (>90% reduction) and no significant change in receptor phosphorylation. This all suggests that factors other than circulating and locally produced IGF-I are responsible for compensatory renal enlargement.


Assuntos
Fator de Crescimento Insulin-Like I/deficiência , Fator de Crescimento Insulin-Like I/metabolismo , Rim/metabolismo , Rim/patologia , Nefrectomia , Animais , Animais Geneticamente Modificados , Western Blotting , Masculino , Camundongos , Tamanho do Órgão , Reação em Cadeia da Polimerase
9.
Growth Horm IGF Res ; 21(5): 285-91, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21865067

RESUMO

OBJECTIVE: We have recently shown increased sensitivity to IGF-I induced signal transduction in kidneys of diabetic mice. Accordingly we investigated the effects of PQ401, a novel diarylurea compound that inhibits IGF1R autophosphorylation in type I diabetes. METHODS: Control (C) and Diabetic (D) mice were administered PQ401 (CP, DP) or vehicle (C, D) for 3weeks. RESULTS: CP animals showed a decrease in renal phosphorylated (p-)AKT and p-IGF1R. However, PQ401 had no effect on diabetic state (hyperglycemia, weight loss) or renal disease parameters (hypertrophy, hyperfiltration and albuminuria). Type IV collagen as well as TGF-ß mRNA increased in DP and D compared to C. In the CP group renal hypertrophy with fat accumulation in proximal tubuli and increased renal IGF-I, collagen IV and TGF-ß mRNA were seen. CONCLUSIONS: IGF1R inhibition by PQ401 exerted no significant effects on diabetic kidney disease parameters, arguing against a role for IGF-I in the pathogenesis of diabetic kidney disease. However, PQ401 affects normal kidneys, inducing renal hypertrophy as well as collagen and fat accumulation, with increased renal IGF-I mRNA, suggestive of a damage-regeneration process. Therefore, this diarylurea compound is not beneficial in early diabetic kidney disease. Its potential deleterious effects on kidney tissue need to be further investigated.


Assuntos
Aminoquinolinas/farmacologia , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/patologia , Compostos de Fenilureia/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Fosforilação/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo
10.
Am J Physiol Endocrinol Metab ; 301(5): E873-81, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21791619

RESUMO

The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.


Assuntos
Leucina/farmacologia , Músculo Esquelético/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Uremia/patologia , Animais , Doença Crônica , Avaliação Pré-Clínica de Medicamentos , Rim/fisiopatologia , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Falência Renal Crônica/patologia , Falência Renal Crônica/fisiopatologia , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/etiologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Uremia/etiologia , Uremia/metabolismo , Uremia/fisiopatologia , Síndrome de Emaciação/etiologia , Síndrome de Emaciação/metabolismo , Síndrome de Emaciação/patologia , Síndrome de Emaciação/fisiopatologia , Suporte de Carga/fisiologia
11.
Kidney Int ; 78(1): 89-95, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20375991

RESUMO

Growth hormone (GH) resistance is common in uremia and together with resistance to insulin-like growth factor-1 (IGF-1) contributes to uremic growth retardation and muscle wasting. Previously, we found decreased GH-stimulated janus-kinase 2-signal transducers and activators of transcription 5 (STAT5) phosphorylation and nuclear translocation in uremia; however, it is unclear whether there are more distal defects. Therefore, we tested whether the binding of phosphorylated STAT5b to DNA is intact in uremia. Using uremic rats we found that in addition to impaired hepatic STAT5b phosphorylation, the binding of available phospho-STAT5b to DNA is decreased thus contributing to impaired IGF-1 gene expression. As sepsis-induced inflammation causes a loss of body protein and as Gram-negative infections are relatively common in uremia, we also characterized mechanisms in which acute inflammation might contribute to GH resistance in uremia. Endotoxin-induced inflammation markedly increased the resistance to GH-mediated STAT5b signaling, and further decreased STAT5b binding to DNA and IGF-1 gene expression. These perturbations appear to be related to increased cytokine expression. Thus, our findings indicate that hepatic resistance to GH-induced IGF-1 expression in uremia arises due to defects in STAT5b phosphorylation and its impaired binding to DNA, processes further aggravated by inflammation.


Assuntos
Hormônio do Crescimento/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Uremia/metabolismo , Animais , DNA/genética , DNA/metabolismo , Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/genética , Hormônio do Crescimento Humano/metabolismo , Inflamação/genética , Inflamação/metabolismo , Fator de Crescimento Insulin-Like I/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Fígado/metabolismo , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT5 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Uremia/genética
12.
Endocrinology ; 150(8): 3620-6, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19443577

RESUMO

Inflammation-induced skeletal muscle wasting is a serious clinical problem and arises in part because of resistance to GH-stimulated IGF-I expression. Although it is established that in the liver, resistance develops because of impaired signaling through the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) transduction pathway, together with a more distal defect in STAT5 DNA-binding activity, the situation in skeletal muscle is unclear. Accordingly, we set out to characterize the mechanisms behind the skeletal muscle resistance to GH in rats with acute inflammation induced by endotoxin. Endotoxin caused significant declines in GH-stimulated STAT5a/b phosphorylation and IGF-I gene expression, and this occurred despite a lack of change in signaling protein levels or phosphorylation of JAK2. In whole muscle, GH-stimulated phospho-STAT5a/b levels were reduced by half, and in the nucleus, phospho-STAT5b levels were similarly reduced. Furthermore, the binding of phosphorylated STAT5b to DNA was reduced and to a similar extent to the reduction in nuclear phosphorylated STAT5b. Interestingly, GH-induced androgen receptor gene expression was also suppressed. Thus, it appears that skeletal muscle resistance to GH-stimulated IGF-I expression in acute endotoxemia arises from a defect in STAT5b signaling, with a proportionate reduction in STAT5b DNA binding. Finally, it appears that resistance to GH-induced androgen receptor expression also develops and, together with the attenuated GH-induced IGF-I expression, likely plays an important role in the muscle wasting that arises in endotoxin-induced inflammation.


Assuntos
Hormônio do Crescimento/farmacologia , Lipopolissacarídeos/farmacologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Animais , Western Blotting , DNA/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Imunoprecipitação , Técnicas In Vitro , Janus Quinase 2/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Reação em Cadeia da Polimerase , Ligação Proteica/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Endocrine ; 36(1): 126-34, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19387875

RESUMO

Growth hormone (GH) and IGF-I have been implicated in the pathogenesis of type I diabetic (DM) nephropathy. We investigated renal GH receptor (GHR) and IGF-type 1 receptor (IGF1R) signaling in an animal model of type I DM. Kidney tissue was examined for GHR and IGF1R key signaling molecules. GHR levels were unchanged and IGF-I mRNA levels were decreased in the diabetic group (D). Basal and GH stimulated phosphorylated (p-) JAK2 and STAT5 levels were similar in controls (C) and D. The levels of p-IGF1R were similar in the two groups at baseline, while pAkt, pGSK3, p-mTOR, p-rpS6, p-erk1/2 (Mapk), and pSTAT-3 were increased in D. Following IGF-I administration p-Akt, p-rpS6, p-Mapk, and p-GSK levels increased more pronouncedly in D versus C. In conclusion, the lack of JAK2-STAT5 activation and the decrease in kidney IGF-I mRNA levels in D argue against a role for the GH activated JAK2-STAT5 pathway in the pathogenesis of diabetic nephropathy. On the other hand while IGF1R phosphorylation was unchanged, Akt/mTOR and MAPK signaling were hyperactivate in DM, suggesting their involvement. The increase in baseline activated Akt, mTOR, rpS6, and MAPK cannot be explained by activation of the IGF1R, but may be triggered by other growth factors and nutrients.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Receptor IGF Tipo 1/metabolismo , Animais , Hormônio do Crescimento/metabolismo , Janus Quinase 2/metabolismo , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Receptor IGF Tipo 1/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Serina-Treonina Quinases TOR
14.
J Am Soc Nephrol ; 19(9): 1774-83, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18650479

RESUMO

Growth hormone (GH) is required to maintain normal cardiac structure and function and has a positive effect on cardiac remodeling in experimental and possibly human disease. Cardiac resistance to GH develops in the uremic state, perhaps predisposing to the characteristic cardiomyopathy associated with uremia. It was hypothesized that administration of low-dosage GH may have a salutary effect on the cardiac remodeling process in uremia, but because high levels of GH have adverse cardiac effects, administration of high-dosage GH may worsen uremic cardiomyopathy. In rats with chronic renal failure, quantitative cardiac morphology revealed a decrease in total capillary length and capillary length density and an increase in mean intercapillary distance and fibroblast volume density evident. Low-dosage GH prevented these changes. Collagen and TGF-beta immunostaining, increased in chronic renal failure, were also reduced by GH, suggesting a mechanism for its salutary action. Low-dosage GH also prevented thickening of the carotid artery but did not affect aortic pathology. In contrast, high-dosage GH worsened several of these variables. These results suggest that low-dosage GH may benefit the heart and possibly the carotid arteries in chronic renal failure.


Assuntos
Cardiomiopatia Hipertrófica/prevenção & controle , Hormônio do Crescimento/administração & dosagem , Miocárdio/patologia , Uremia/complicações , Remodelação Ventricular/efeitos dos fármacos , Animais , Artérias/patologia , Pressão Sanguínea , Peso Corporal , Cardiomiopatia Hipertrófica/etiologia , Cardiomiopatia Hipertrófica/patologia , Expressão Gênica , Hematócrito , Hemodinâmica , Imuno-Histoquímica , Masculino , Miocárdio/metabolismo , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Uremia/sangue , Uremia/patologia
15.
Am J Physiol Endocrinol Metab ; 292(6): E1856-62, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17327369

RESUMO

Gram-negative sepsis with release of endotoxin is a frequent cause of cachexia that develops partly because of resistance to growth hormone (GH) with reduced insulin-like growth factor-I (IGF-I) expression. We set out to more fully characterize the mechanisms for the resistance and to determine whether in addition to a defect in the janus kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) 5b pathway, required for GH-induced IGF-I expression, there might also be a more distal defect. Conscious rats were given endotoxin and studied 4 h later. In liver of these animals, GH-induced JAK2 and STAT5 phosphorylation was impaired and appeared to be caused, at least in part, by a marked increase in hepatic tumor necrosis factor-alpha and interleukin-6 mRNA expression accompanied by elevated levels of inhibitors of GH signaling, namely cytokine-inducible suppressors of cytokine signaling-1 and -3 and cytokine-inducible SH2 protein (CIS). Nuclear phosphorylated STAT5b levels were significantly depressed to 61% of the control values and represent a potential cause of the reduced GH-induced IGF-I expression. In addition, binding of phosphorylated STAT5b to DNA was reduced to an even greater extent and averaged 17% of the normal control value. This provides a further explanation for the impaired IGF-I gene transcription. Interestingly, when endotoxin-treated rats were treated with GH, there was a marked increase in proinflammatory cytokine gene expression in the liver. If such a response were to occur in humans, this might provide a partial explanation for the adverse effect of GH treatment reported in critically ill patients.


Assuntos
DNA/metabolismo , Endotoxinas/farmacologia , Hormônio do Crescimento/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Janus Quinase 2/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Doença Aguda , Animais , Citocinas/genética , DNA/antagonistas & inibidores , Endotoxemia/metabolismo , Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Fator de Crescimento Insulin-Like I/genética , Fígado/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Supressoras da Sinalização de Citocina/genética , Transcrição Genética/efeitos dos fármacos
16.
PLoS Genet ; 2(7): e115, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16789832

RESUMO

We analyzed expression of 81 normal muscle samples from humans of varying ages, and have identified a molecular profile for aging consisting of 250 age-regulated genes. This molecular profile correlates not only with chronological age but also with a measure of physiological age. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in the kidney and the brain, and found a common signature for aging in these diverse human tissues. The common aging signature consists of six genetic pathways; four pathways increase expression with age (genes in the extracellular matrix, genes involved in cell growth, genes encoding factors involved in complement activation, and genes encoding components of the cytosolic ribosome), while two pathways decrease expression with age (genes involved in chloride transport and genes encoding subunits of the mitochondrial electron transport chain). We also compared transcriptional profiles of aging in humans to those of the mouse and fly, and found that the electron transport chain pathway decreases expression with age in all three organisms, suggesting that this may be a public marker for aging across species.


Assuntos
Envelhecimento , Perfilação da Expressão Gênica , Músculos/patologia , Transcrição Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores/metabolismo , Drosophila , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade
17.
J Ren Nutr ; 16(2): 141-9, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16567271

RESUMO

BACKGROUND: Resistance to growth hormone (GH) in end-stage renal disease (ESRD) causes growth retardation and muscle wasting. In humans, circulating GH binding protein (GHBP), the extracellular domain of the GH receptor that is shed into the circulation and is believed to reflect tissue GH receptor levels, is reduced in uremia and suggests that cellular GH receptor levels are correspondingly reduced. If true, this could be a cause of GH resistance. We set out to establish whether serum GHBP levels reflect cellular GH receptor levels and whether changes in serum GHBP levels are related to nutritional or inflammatory status. METHODS: GH receptor protein expression in peripheral blood mononuclear cells (PBMC) from 21 ESRD and 14 normal subjects were analyzed by fluorochrome flow cytometry. RESULTS: The GH receptor density and percent total PBMCs expressing the GH receptor were similar in the 2 groups, and there was no difference in percent GH receptor positive T or B cells or monocytes. In contrast, serum GHBP levels were 80% lower in ESRD. GHBP levels did not correlate with serum albumin, body mass index, or muscle mass but seemed to be partly related to the log serum C-reactive protein levels. CONCLUSIONS: Serum GHBP levels are markedly reduced in ESRD; this seems to occur independent of nutritional status and may in part be caused by inflammation. Because GH receptor expression on PBMC of ESRD and control subjects was similar, our findings argue against a reduction in GH receptor as a cause of GH resistance and the use of serum GHBP levels as a reliable marker of specific tissue GH receptor levels.


Assuntos
Falência Renal Crônica/sangue , Leucócitos Mononucleares/química , Receptores da Somatotropina/sangue , Adulto , Idoso , Antropometria , Linfócitos B/química , Índice de Massa Corporal , Proteína C-Reativa/análise , Separação Celular , Feminino , Citometria de Fluxo , Hormônio do Crescimento Humano/sangue , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/análise , Fator de Crescimento Insulin-Like I/análise , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Albumina Sérica/análise , Linfócitos T/química
18.
Pediatr Nephrol ; 20(3): 313-8, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15692835

RESUMO

Resistance to growth hormone (GH) is a significant complication of advanced chronic renal failure. Thus while the circulating GH levels are normal or even elevated in uremia, resistance to the hormone leads to stunting of body growth in children and contributes to muscle wasting in adults. Insensitivity to GH is the consequence of multiple defects in the GH/insulin-like growth factor-1 (IGF-1) system. Expression of the GH receptor may be reduced, although this is not a consistent finding, GH activation of the Janus kinase 2-signal transducer (JAK2) and activator of transcription (STAT) signal transduction pathway is depressed and this leads to reduced IGF-1 expression, and finally there is resistance to IGF-1, a major mediator of GH action. We review these various defects with an emphasis on the GH-activated JAK2-STAT5 pathway, since this pathway is essential for normal body growth and there has been recent progress in our understanding of the perturbations that occur in uremia.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Hormônio do Crescimento/fisiologia , Proteínas Tirosina Quinases/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Transativadores/fisiologia , Uremia/fisiopatologia , Criança , Humanos , Fator de Crescimento Insulin-Like I/fisiologia , Janus Quinase 2 , Falência Renal Crônica/fisiopatologia , Proteínas do Leite , Receptores da Somatotropina/fisiologia , Fator de Transcrição STAT5
19.
Kidney Int ; 67(3): 858-66, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15698425

RESUMO

BACKGROUND: Cardiovascular disease is a major cause of death in end-stage renal disease (ESRD). Since growth hormone is required for maintaining normal cardiac structure and function and as growth hormone has a salutary effect on cardiac remodeling in disease, we postulated that if cardiac resistance to growth hormone develops in chronic renal failure (CRF) this may predispose to the cardiomyopathy of uremia. We set out to test whether in CRF there is resistance to the cardiac action of growth hormone and whether this defect might be caused by altered growth hormone signaling. METHODS: Growth hormone-deficient (dw/dw) rats and growth hormone-intact Sprague-Dawley rats underwent a subtotal nephrectomy or sham operation and pair feeding. RESULTS: In dw/dw rats treated with growth hormone for 8 days there was a significant increase in insulin-like growth factor-1 (IGF-1) mRNA levels in controls but this response was attenuated in CRF. Next, growth hormone-stimulated Janus kinase-signal transducers and activators of transcription (JAK2-STAT5) signaling was studied 15 minutes after intravenous growth hormone in dw/dw and Sprague-Dawley rats. Growth hormone receptor, JAK2, STAT5a, and STAT5b protein levels were unaltered in CRF. Growth hormone-induced JAK2, growth hormone receptor (GHR), and STAT5 tyrosine phosphorylation was significantly depressed in CRF as was nuclear translocation of phosphorylated STAT5. When rats were treated with pharmacologic dose growth hormone, STAT5 phosphorylation increased similarly in CRF and control rats. CONCLUSION: Uremic rats develop cardiac resistance to growth hormone caused at least, in part, by a postreceptor defect in growth hormone-induced signaling that is characterized by impaired phosphorylation and nuclear translocation of STAT5. These findings raise the question whether growth hormone resistance contributes to the cardiac changes of uremia.


Assuntos
Hormônio do Crescimento/farmacologia , Coração/efeitos dos fármacos , Uremia/metabolismo , Animais , Doenças Cardiovasculares/etiologia , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/fisiologia , Fator de Crescimento Insulin-Like I/genética , Janus Quinase 2 , Masculino , Proteínas do Leite/análise , Miocárdio/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Quinases/análise , Proteínas Tirosina Quinases/fisiologia , Proteínas Proto-Oncogênicas/análise , Proteínas Proto-Oncogênicas/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores da Somatotropina/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT5 , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina , Transativadores/análise , Transativadores/fisiologia , Uremia/complicações
20.
Pediatr Nephrol ; 20(5): 567-75, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15723195

RESUMO

Cytokines consist of a large family of secreted proteins, including pro-inflammatory agents, growth hormone and erythropoietin, that utilize the Janus kinase (JAK) signal transducer and activator of transcription (STAT) signal transduction pathway to mediate many of their key physiologic and pathologic actions. These actions include cytokine-mediated inflammation, immunoregulation, hematopoiesis and growth. The JAK-STAT pathway is regulated by several processes, among which negative feedback regulation by the suppressors of cytokine signaling (SOCS), members of a family of eight proteins, is particularly important. Each cytokine induces one or more specific SOCS proteins that in turn down-regulate the signal initiated by the cytokine. Through their impact on the cytokine-activated JAK-STAT pathway, the SOCS proteins are involved in many diseases that come to the attention of the pediatric nephrologist. For example, an increase in the expression of SOCS-2 and -3 may be a cause of growth hormone resistance and thus may contribute to the growth retardation that affects children with chronic renal failure. Because of their obvious biologic importance, the SOCS proteins have been the subject of intense research that includes the development of strategies to utilize these proteins to control cytokine-induced JAK/STAT signal transduction for therapeutic purposes.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Nefropatias/fisiopatologia , Proteínas Repressoras/fisiologia , Fatores de Transcrição/fisiologia , Animais , Criança , Humanos , Proteína 1 Supressora da Sinalização de Citocina , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina
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